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  • 1.
    Brunk, Ulf
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Lipofuscin: Mechanisms of age-related accumulation and influence on cell function2002In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 33, no 5, p. 611-619Article in journal (Refereed)
    Abstract [en]

    The accumulation of lipofuscin within postmitotic cells is a recognized hallmark of aging occuring with a rate inversely related to longevity. Lipofuscin is an intralysosomal, polymeric substance, primarily composed of cross-linked protein residues, formed due to iron-catalyzed oxidative processes. Because it is undegradable and cannot be removed via exocytosis, lipofuscin accumulation in postmitotic cells is inevitable, whereas proliferative cells efficiently dilute it during division. The rate of lipofuscin formation can be experimentally manipulated. In cell culture models, oxidative stress (e.g., exposure to 40% ambient oxygen or low molecular weight iron) promotes lipofuscin accumulation, whereas growth at 8% oxygen and treatment with antioxidants or iron-chelators diminish it. Lipofuscin is a fluorochrome and may sensitize lysosomes to visible light, a process potentially important for the pathogenesis of age-related macular degeneration. Lipofuscin-associated iron sensitizes lysosomes to oxidative stress, jeopardizing lysosomal stability and causing apoptosis due to release of lysosomal contents. Lipofuscin accumulation may also diminish autophagocytotic capacity by acting as a sink for newly produced lysosomal enzymes and, therefore, interfere with recycling of cellular components. Lipofuscin, thus, may be much more directly related to cellular degeneration at old age than was hitherto believed.

  • 2.
    Brunk, Ulf
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    The mitochondrial-lysosomal axis theory of aging: Accumulation of damaged mitochondria as a result of imperfect autophagocytosis2002In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 269, no 8, p. 1996-2002Article in journal (Refereed)
    Abstract [en]

    Cellular manifestations of aging are most pronounced in postmitotic cells, such as neurons and cardiac myocytes. Alterations of these cells, which are responsible for essential functions of brain and heart, are particularly important contributors to the overall aging process. Mitochondria and lysosomes of postmitotic cells suffer the most remarkable age-related alterations of all cellular organelles. Many mitochondria undergo enlargement and structural disorganization, while lysosomes, which are normally responsible for mitochondrial turnover, gradually accumulate an undegradable, polymeric, autofluorescent material called lipofuscin, or age pigment. We believe that these changes occur not only due to continuous oxidative stress (causing oxidation of mitochondrial constituents and autophagocytosed material), but also because of the inherent inability of cells to completely remove oxidatively damaged structures (biological 'garbage'). A possible factor limiting the effectiveness of mitochondial turnover is the enlargement of mitochondria which may reflect their impaired fission. Non-autophagocytosed mitochondria undergo further oxidative damage, resulting in decreasing energy production and increasing generation of reactive oxygen species. Damaged, enlarged and functionally disabled mitochondria gradually displace normal ones, which cannot replicate indefinitely because of limited cell volume. Although lipofuscin-loaded lysosomes continue to receive newly synthesized lysosomal enzymes, the pigment is undegradable. Therefore, advanced lipofuscin accumulation may greatly diminish lysosomal degradative capacity by preventing lysosomal enzymes from targeting to functional autophagosomes, further limiting mitochondrial recycling. This interrelated mitochondrial and lysosomal damage irreversibly leads to functional decay and death of postmitotic cells.

  • 3.
    Cuervo, Ana Maria
    et al.
    Albert Einstein College of Medicine.
    Bergamini, Ettore
    University of Pisa.
    Brunk, Ulf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Droge, Wolf
    Heidelberg, Germany.
    Ffrench, Martine
    Central Hospital, Lyon.
    Terman, Alexei
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences.
    Autophagy and aging - The importance of maintaining "clean" cells2005In: autophagy, Vol. 1, no 3, p. 131-140Article, review/survey (Refereed)
    Abstract [en]

    A decrease in the turnover of cellular components and the intracellular accumulation of altered macromolecules and organelles are features common to all aged cells. Diminished autophagic activity plays a major role in these age-related manifestations. In this work we review the molecular defects responsible for the malfunctioning of two forms of autophagy, macroautophagy and chaperone-mediated outophagy, in old mammals, and highlight general and cell-type specific consequences of dysfunction of the autophagic system with age. Dietary caloric restriction and antilipolytic agents have been proven to efficiently stimulate autophagy in old rodents. These and other possible experimental restorative efforts are discussed.

  • 4.
    Klionsky, Daniel J.
    et al.
    University of Michigan, USA.
    Abeliovich, Hagai
    Hebrew University of Jerusalem, Israel.
    Agostinis, Patrizia
    Catholic University of Louvain, Belgium.
    Agrawal, Devendra K.
    Creighton University, USA.
    Aliev, Giumrakch
    University of Texas San Antonio, TX USA.
    S. Askew, David
    University of Cincinnati, USA.
    Baba, Misuzu
    Japan Womens University, Japan.
    H. Baehrecke, Eric
    University of Massachusetts, MA USA.
    A. Bahr, Ben
    University of Connecticut, CT USA.
    Ballabio, Andrea
    Telethon Institute Genet and Med, Italy.
    A. Bamber, Bruce
    University of Toledo, OH 43606 USA .
    C. Bassham, Diane
    Iowa State University, IA USA Iowa State University, IA USA .
    Bergamini, Ettore
    University of Pisa, Italy .
    Bi, Xiaoning
    Western University of Health Science, CA USA .
    Biard-Piechaczyk, Martine
    UM2, France .
    S. Blum, Janice
    Indiana University, IN 46202 USA .
    E. Breclesen, Dale
    Bucks Institute Age Research, CA USA .
    L. Brodsky, Jeffrey
    University of Pittsburgh, PA 15260 USA Massachusetts Gen Hospital, MA USA .
    H. Brumell, John
    Hospital Sick Children, Canada .
    Brunk, Ulf T.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bursch, Wilfried
    Medical University of Vienna, Austria .
    Camougrand, Nadine
    University of Bordeaux 2, France .
    Cebollero, Eduardo
    CSIC, Spain .
    Cecconi, Francesco
    University of Roma Tor Vergata, Italy University of Roma Tor Vergata, Italy .
    Chen, Yingyu
    Peking University, Peoples R China .
    Chin, Lih-Shen
    Emory University School of Medicine.
    Choi, Augustine
    Emory University, GA 30322 USA .
    T. Chu, Charleen
    Harvard University, MA USA.
    Chung, Jongkyeong
    University of Pittsburgh, PA USA Korea Adv Institute Science and Technology, South Korea .
    G. H. Clarke, Peter
    University of Lausanne, Switzerland .
    S. B. Clark, Robert
    Safar Centre Resuscitat Research, PA USA .
    G. Clarke, Steven
    University of Calif Los Angeles, CA 90024 USA University of Calif Los Angeles, CA 90024 USA .
    Clave, Corinne
    University of Bordeaux 2, France .
    L. Cleveland, John
    Scripps Research Institute, FL USA .
    Codogno, Patrice
    University of Paris 11, France INSERM, France .
    I. Colombo, Maria
    University of Nacl Cuyo, Argentina .
    Coto-Montes, Ana
    University of Oviedo, Spain .
    M. Cregg, James
    Keck Grad Institute Appl Science, CA USA .
    Maria Cuervo, Ana
    Albert Einstein Coll Med, NY 10467 USA .
    Debnath, Jayanta
    University of Calif San Francisco, CA USA .
    Demarchi, Francesca
    Lab Nazl Consorzio Interuniv Biotecnol, Italy University of Cincinnati, OH USA .
    B. Dennis, Patrick
    USN Medical Oncol, MD 20892 USA .
    A. Dennis, Phillip
    USN Medical Oncol, MD 20892 USA .
    Deretic, Vojo
    University of New Mexico, NM 87131 USA .
    J. Devenish, Rodney
    Monash University, Australia Monash University, Australia .
    Di Sano, Federica
    University of Roma Tor Vergata, Italy .
    Fred Dice, J.
    Tufts University, MA 02111 USA .
    DiFiglia, Marian
    Massachusetts Gen Hospital, MA USA .
    Dinesh-Kumar, Savithramma
    Yale University, CT USA .
    W. Distelhorst, Clark
    Case Western Reserve University, OH 44106 USA Case Western Reserve University, OH 44106 USA University Hospital Cleveland, OH 44106 USA Case Western Reserve University, OH 44106 USA .
    Djavaheri-Mergny, Mojgan
    University of Paris 11, France INSERM, France .
    C. Dorsey, Frank
    The Scripps Research Institute.
    Droege, Wulf
    Immunotec Research Ltd, Canada .
    Dron, Michel
    INRA, France .
    A. Jr. Dunn, William
    University of Florida, FL USA .
    Duszenko, Michael
    University of Tubingen, Germany .
    Tony Eissa, N.
    Baylor University, TX 77030 USA .
    Elazar, Zvulun
    Weizmann Institute Science, Israel .
    Esclatine, Audrey
    University of Paris 11, France INSERM, France .
    Eskelinen, Eeva-Liisa
    University of Helsinki, Finland .
    Fesues, Laszlo
    University of Debrecen, Hungary University of Debrecen, Hungary .
    D. Finley, Kim
    Salk Institute Biol Studies, CA USA .
    M. Fuentes, Jose
    University of Extremadura, Spain .
    Fueyo, Juan
    University of Texas Houston, TX 77030 USA .
    Fujisaki, Kozo
    Kagoshima University, Japan .
    Galliot, Brigitte
    University of Geneva, Switzerland .
    Gao, Fen-Biao
    University of Calif San Francisco, CA 94143 USA University of Calif San Francisco, CA 94143 USA .
    A. Gewirtz, David
    Virginia Commonwealth University, VA USA Virginia Commonwealth University, VA USA .
    B. Gibson, Spencer
    Manitoba Institute Cell Biol, Canada .
    Gohla, Antje
    University of Dusseldorf, Germany .
    L. Goldberg, Alfred
    Harvard University, MA USA .
    Gonzalez, Ramon
    CSIC, Spain .
    Gonzalez-Estevez, Cristina
    University of Nottingham, England .
    Gorski, Sharon
    British Columbia Cancer Agency, Canada .
    A. Gottlieb, Roberta
    San Diego State University, CA 92182 USA .
    Haussinger, Dieter
    University of Dusseldorf, Germany .
    He, You-Wen
    Duke University, NC USA .
    Heidenreich, Kim
    University of Colorado, CO USA .
    A. Hill, Joseph
    University of Texas SW Medical Centre Dallas, TX 75390 USA .
    Hoyer-Hansen, Maria
    Danish Cancer Soc, Denmark Danish Cancer Soc, Denmark .
    Hu, Xun
    Zhejiang University, Peoples R China .
    Huang, Wei-Pang
    National Taiwan University, Taiwan .
    Iwasaki, Akiko
    Yale University, CT USA .
    Jaattela, Marja
    University of Debrecen, Hungary University of Debrecen, Hungary .
    T. Jackson, William
    Medical Coll Wisconsin, WI 53226 USA .
    Jiang, Xuejun
    Mem Sloan Kettering Cancer Centre, NY 10021 USA .
    Jin, Shengkan
    University of Medical and Dent New Jersey, NJ 08854 USA .
    Johansen, Terje
    University of Tromso, Norway .
    U. Jung, Jae
    University of So Calif, CA USA .
    Kadowaki, Motoni
    Niigata University, Japan .
    Kang, Chanhee
    University of Texas SW Medical Centre Dallas, TX 75390 USA .
    Kelekar, Ameeta
    University of Minnesota, MN USA .
    H. Kessel, David
    Wayne State University, MI USA .
    A. K. W. Kiel, Jan
    University of Groningen, Netherlands .
    Pyo Kim, Hong
    University of Pittsburgh, PA USA .
    Kimchi, Adi
    Weizmann Institute Science, Israel .
    J. Kinsella, Timothy
    University Hospital Cleveland, OH 44106 USA .
    Kiselyov, Kirill
    University of Pittsburgh, PA 15260 USA .
    Kitamoto, Katsuhiko
    University of Tokyo, Japan .
    Knecht, Erwin
    Centre Invest Principe Felipe, Spain .
    Komatsu, Masaaki
    Tokyo Metropolitan Institute Medical Science, Japan .
    Kominami, Eiki
    Juntendo University, Japan .
    Kondo, Seiji
    University of Texas MD Anderson Cancer Center.
    L. Kovacs, Attila
    University of Texas MD Anderson Cancer Centre, TX USA .
    Kroemer, Guido
    Eotvos Lorand University, Hungary Institute Gustave Roussy, France University of Paris 11, France .
    Kuan, Chia-Yi
    Cincinnati Childrens Hospital Research Fdn, OH USA .
    Kumar, Rakesh
    University of Penn, PA 19104 USA .
    Kundu, Mondira
    University of Laval, Canada .
    Landry, Jacques
    Eastern Michigan University, MI 48197 USA .
    Laporte, Marianne
    Eastern Michigan University.
    Le, Weidong
    Shanghai Jiao Tong University, Peoples R China Chinese Academic Science, Peoples R China .
    Lei, Huan-Yao
    National Cheng Kung University, Taiwan .
    J. Lenardo, Michael
    NIAID, MD USA .
    Levine, Beth
    University of Texas SW Medical Centre Dallas, TX 75390 USA University of Texas SW Medical Centre Dallas, TX 75390 USA .
    Lieberman, Andrew
    University of Michigan, MI USA .
    Lim, Kah-Leong
    National Institute Neurosci, Singapore .
    Lin, Fu-Cheng
    Zhejiang University, Peoples R China .
    Liou, Willisa
    Chang Gung University.
    F. Liu, Leroy
    University of Medical and Dent New Jersey, NJ 08854 USA National Research Centre Environm and Heatlh, Germany .
    Lopez-Berestein, Gabriel
    University of Texas MD Anderson Cancer Centre, TX USA .
    Lopez-Otin, Carlos
    University of Oviedo, Spain .
    Lu, Bo
    Vanderbilt University, TN USA .
    F. Macleod, Kay
    University of Chicago, IL 60637 USA Ist Super Sanita, Italy .
    Malorni, Walter
    Istituto Superiore di Sanita.
    Martinet, Wim
    University of Antwerp, Belgium .
    Matsuoka, Ken
    Kyushu University, Japan .
    Mautner, Josef
    GSF-National Research Center for Environment and Health.
    J. Meijer, Alfred
    University of Amsterdam, Netherlands .
    Melendez, Alicia
    CUNY, NY USA .
    Michels, Paul
    Catholic University of Louvain, Belgium Catholic University of Louvain, Belgium .
    Miotto, Giovanni
    University of Padua, Italy .
    P. Mistiaen, Wilhelm
    University of Coll Antwerp, Belgium .
    Mizushima, Noboru
    Tokyo Medical and Dent University, Japan .
    Mograbi, Baharia
    INSERM, France IFR 50, France .
    Monastyrska, Iryna
    University of Utrecht, Netherlands .
    N. Moore, Michael
    Plymouth Marine Lab, England .
    I. Moreira, Paula
    Centre Neurosci and Cell Biol, Portugal .
    Moriyasu, Yuji
    Saitama University, Japan .
    Motyl, Tomasz
    Agriculture University of Warsaw, Poland .
    Muenz, Christian
    Rockefeller University, NY 10021 USA .
    O. Murphy, Leon
    Novartis Institute Biomed Research, MA USA .
    I. Naqvi, Naweed
    National University of Singapore, Singapore .
    Neufeld, Thomas
    University of Minnesota.
    Nishino, Ichizo
    National Centre Neurol and Psychiat, Japan .
    A. Nixon, Ralph
    NYU, NY USA .
    Noda, Takeshi
    Osaka University, Japan .
    Nuernberg, Bernd
    University of Dusseldorf, Germany .
    Ogawa, Michinaga
    University of Tokyo, Japan .
    L. Oleinick, Nancy
    Case Western Reserve University, OH USA Case Western Reserve University, OH 44106 USA Case Western Reserve University, OH 44106 USA Case Western Reserve University, OH 44106 USA .
    J. Olsen, Laura
    University of Michigan, MI 48109 USA .
    Ozpolat, Bulent
    University of Texas MD Anderson Cancer Centre, TX USA .
    Paglin, Shoshana
    Chaim Sheba Medical Centre, Israel .
    E. Palmer, Glen
    Louisiana State University, LA USA .
    Papassideri, Issidora
    Department Cell Biol and Biophys, Greece .
    Parkes, Miles
    University of Cambridge, England .
    H. Perlmutter, David
    University of Pittsburgh, PA 15261 USA Childrens Hospital Pittsburgh, PA 15213 USA .
    Perry, George
    University of Texas San Antonio, TX USA .
    Piacentini, Mauro
    University of Roma Tor Vergata, Italy .
    Pinkas-Kramarski, Ronit
    Tel Aviv University, Israel .
    Prescott, Mark
    Monash University, Australia .
    Proikas-Cezanne, Tassula
    University of Tubingen, Germany .
    Raben, Nina
    NIAMSD, MD USA .
    Rami, Abdelhaq
    Clin JWG University, Germany .
    Reggiori, Fulvio
    University of Utrecht, Netherlands .
    Rohrer, Baerbel
    Medical University of S Carolina, SC 29425 USA .
    C. Rubinsztein, David
    Cambridge Institute Medical Research, England .
    M. Ryan, Kevin
    Beatson Institute Cancer Research, Scotland .
    Sadoshima, Junichi
    University of Medical and Dent New Jersey, NJ 07103 USA .
    Sakagami, Hiroshi
    Meikai University, Japan .
    Sakai, Yasuyoshi
    Kyoto University, Japan JST, Japan .
    Sandri, Marco
    University of Padua, Italy Venetan Institute Molecular Med, Italy .
    Sasakawa, Chihiro
    University of Tokyo, Japan .
    Sass, Miklos
    University of Oslo, Norway .
    Schneider, Claudio
    Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie.
    O. Seglen, Per
    University of Wyoming, WY 82071 USA .
    Seleverstov, Oleksandr
    University of Oslo, Norway .
    Settleman, Jeffre
    Massachusetts General Hospital Cancer Center.
    J. Shacka, John
    University of Alabama Birmingham, AL 35294 USA .
    M. Shapiro, Irving
    Thomas Jefferson University, PA 19107 USA .
    Sibirny, Andrei
    National Academic Science Ukraine, Ukraine .
    C. M. Silva-Zacarin, Elaine
    University of Federal Sao Carlos, Brazil .
    Simon, Hans-Uwe
    University of Bern, Switzerland .
    Simone, Cristiano
    Ist Ric Farmacol Mario Negri, Italy .
    Simonsen, Anne
    University of Oslo, Norway Norwegian Radium Hospital, Norway .
    A. Smith, Mark
    Case Western Reserve University, OH 44106 USA .
    Spanel-Borowski, Katharina
    University of Leipzig, Germany .
    Srinivas, Vickram
    Thomas Jefferson University, PA 19107 USA .
    Steeves, Meredith
    Scripps Research Institute, FL USA .
    Stenmark, Harald
    Norwegian Radium Hospital, Norway .
    E. Stromhaug, Per
    University of Missouri, MO USA .
    S. Subauste, Carlos
    Case Western Reserve University, OH USA Case Western Reserve University, OH USA .
    Sugimoto, Seiichiro
    National Hospital Org, Japan .
    Sulzer, David
    Columbia University, NY USA Columbia University, NY USA .
    Suzuki, Toshihiko
    University of Ryukyus, Japan .
    S. Swanson, Michele
    University of Michigan, MI 48109 USA .
    Takeshita, Fumihiko
    Yokohama City University, Japan .
    J. Talbot, Nicholas.
    University of Exeter, England .
    Talloczy, Zsolt
    Columbia University, NY USA Columbia University, NY USA .
    Tanaka, Keiji
    Tokyo Metropolitan Institute Medical Science, Japan Tohoku University, Japan .
    Tanaka, Kozo
    Tokyo Metropolitan Institute Medical Science, Japan Tohoku University, Japan .
    Tanida, Isei
    National Institute Infect Disease, Japan .
    S. Taylor, Graham
    University of Birmingham, England .
    Paul Taylor, J.
    University of Penn, PA 19104 USA .
    Terman, Alexei
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Tettamanti, Gianluca
    University of Insubria, Italy .
    B. Thompson, Craig
    University of Penn, PA 19104 USA .
    Thumm, Michael
    University of Gottingen, Germany .
    M. Tolkovsky, Aviva
    University of Cambridge, England .
    A. Tooze, Sharon
    Cancer Research UK London Research Institute, England .
    Truant, Ray
    McMaster University, Canada .
    V. Tumanovska, Lesya
    AA Bogomolets Physiol Institute, Ukraine .
    Uchiyama, Yasuo
    Osaka University, Japan .
    Ueno, Takashi
    Juntendo University, Japan .
    L. Uzcategui, Nestor
    Central University of Venezuela, Venezuela .
    van der Klei, Ida
    University of Groningen, Netherlands .
    C. Vaquero, Eva
    Hospital Clin Barcelona, Spain .
    Vellai, Tibor
    Eotvos Lorand University, Hungary .
    W. Vogel, Michael
    Maryland Psychiat Research Centre, MD 21228 USA .
    Wang, Hong-Gang
    H Lee Moffitt Cancer Centre and Research Institute, FL USA .
    Webster, Paul
    House Ear Research Institute, CA USA .
    W. Wiley, John
    University of Michigan, MI 48109 USA .
    Xi, Zhijun
    Peking University, Peoples R China .
    Xiao, Gutian
    University of Pittsburgh, PA USA .
    Yahalom, Joachim
    Memorial Sloan-Kettering Cancer Center.
    Yang, Jin-Ming
    University of Medical and Dent New Jersey, NJ USA .
    Yap, George
    University of Medical and Dent New Jersey, NJ 07103 USA .
    Yin, Xiao-Min
    University of Pittsburgh, PA USA .
    Yoshimori, Tamotsu
    Osaka University, Japan .
    Yu, Li
    NIAID, MD USA .
    Yue, Zhenyu
    Mt Sinai School Med, NY USA .
    Yuzaki, Michisuke
    Keio University, Japan .
    Zabirnyk, Olga
    NCI, MD USA National Institute Heatlh, MD USA .
    Zheng, Xiaoxiang
    Zhejiang University, Peoples R China .
    Zhu, Xiongwei
    Case Western Reserve University, OH 44106 USA .
    L. Deter, Russell
    Baylor University, TX 77030 USA .
    Tabas, Ira
    Columbia University, NY USA .
    Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes2008In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 4, no 2, p. 151-175Article, review/survey (Refereed)
    Abstract [en]

    Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.

  • 5.
    Kurz, Tino
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Autophagy, ageing and apoptosis: The role of oxidative stress and lysosomal iron2007In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 462, no 2, p. 220-230Article in journal (Refereed)
    Abstract [en]

    As an outcome of normal autophagic degradation of ferruginous materials, such as ferritin and mitochondrial metalloproteins, the lysosomal compartment is rich in labile iron and, therefore, sensitive to the mild oxidative stress that cells naturally experience because of their constant production of hydrogen peroxide. Diffusion of hydrogen peroxide into the lysosomes results in Fenton-type reactions with the formation of hydroxyl radicals and ensuing peroxidation of lysosomal contents with formation of lipofuscin that amasses in long-lived postmitotic cells. Lipofuscin is a non-degradable polymeric substance that forms at a rate that is inversely related to the average lifespan across species and is built up of aldehyde-linked protein residues. The normal accumulation of lipofuscin in lysosomes seems to reduce autophagic capacity of senescent postmitotic cells-probably because lipofuscin-loaded lysosomes continue to receive newly formed lysosomal enzymes, which results in lack of such enzymes for autophagy. The result is an insufficient and declining rate of autophagic turnover of worn-out and damaged cellular components that consequently accumulate in a way that upsets normal metabolism. In the event of a more substantial oxidative stress, enhanced formation of hydroxyl radicals within lysosomes jeopardizes the membrane stability of particularly iron-rich lysosomes, specifically of autophagolysosomes that have recently participated in the degradation of iron-rich materials. For some time, the rupture of a limited number of lysosomes has been recognized as an early upstream event in many cases of apoptosis, particularly oxidative stress-induced apoptosis, while necrosis results from a major lysosomal break. Consequently, the regulation of the lysosomal content of redox-active iron seems to be essential for the survival of cells both in the short- and the long-term. © 2007 Elsevier Inc. All rights reserved.

  • 6.
    Kurz, Tino
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Lysosomes and oxidative stress in aging and apoptosis2008In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1780, no 11, p. 1291-1303Article in journal (Refereed)
    Abstract [en]

    The lysosomal compartment consists of numerous acidic vesicles (pH ~ 4-5) that constantly fuse and divide. It receives a large number of hydrolases from the trans-Golgi network, while their substrates arrive from both the cell's outside (heterophagy) and inside (autophagy). Many macromolecules under degradation inside lysosomes contain iron that, when released in labile form, makes lysosomes sensitive to oxidative stress. The magnitude of generated lysosomal destabilization determines if reparative autophagy, apoptosis, or necrosis will follow. Apart from being an essential turnover process, autophagy is also a mechanism for cells to repair inflicted damage, and to survive temporary starvation. The inevitable diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow oxidative formation of lipofuscin in long-lived postmitotic cells, where it finally occupies a substantial part of the volume of the lysosomal compartment. This seems to result in a misdirection of lysosomal enzymes away from autophagosomes, resulting in depressed autophagy and the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. This scenario might put aging into the category of autophagy disorders. © 2008 Elsevier B.V. All rights reserved.

  • 7.
    Kurz, Tino
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Terman, Alexei
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Gustafsson, Bertil
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf T.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lysosomes In Iron Metabolism, Ageing And Apoptosis2008In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 129, no 4, p. 389-406Article in journal (Refereed)
    Abstract [en]

    The lysosomal compartment is essential for a variety of cellular functions, including the normal turnover of most long-lived proteins and all organelles. The compartment consists of numerous acidic vesicles (pH ~4-5) that constantly fuse and divide. It receives a large number of hydrolases (~50) from the trans-Golgi network, and substrates from both the cells’ outside (heterophagy) and inside (autophagy). Many macromolecules contain iron that gives rise to an iron-rich environment in lysosomes that recently have degraded such macromolecules. Iron-rich lysosomes are sensitive to oxidative stress, while ‘resting’ lysosomes, which have not recently participated in autophagic events, are not. The magnitude of oxidative stress determines the degree of lysosomal destabilization and, consequently, whether arrested growth, reparative autophagy, apoptosis, or necrosis will follow. Heterophagy is the first step in the process by which immunocompetent cells modify antigens and produce antibodies, while exocytosis of lysosomal enzymes may promote tumor invasion, angiogenesis, and metastasis. Apart from being an essential turnover process, autophagy is also a mechanism by which cells will be able to sustain temporary starvation and rid themselves of intracellular organisms that have invaded, although some pathogens have evolved mechanisms to prevent their destruction. Mutated lysosomal enzymes are the underlying cause of a number of lysosomal storage diseases involving the accumulation of materials that would be the substrate for the corresponding hydrolases, were they not defective. The normal, low-level diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow formation of lipofuscin in long-lived postmitotic cells, where it occupies a substantial part of the lysosomal compartment at the end of the life span. This seems to result in the diversion of newly produced lysosomal enzymes away from autophagosomes, leading to the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. If autophagy were a perfect turnover process, postmitotic ageing and several age-related neurodegenerative diseases would, perhaps, not take place.

  • 8.
    Navratil, M.
    et al.
    Department of Chemistry, University of Minnesota, 207 Pleasant St. SE, Minneapolis, MN, United States.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Arriaga, E.A.
    Department of Chemistry, University of Minnesota, 207 Pleasant St. SE, Minneapolis, MN, United States.
    Giant mitochondria do not fuse and exchange their contents with normal mitochondria2008In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 314, no 1, p. 164-172Article in journal (Refereed)
    Abstract [en]

    Giant mitochondria accumulate within aged or diseased postmitotic cells as a consequence of insufficient autophagy, which is normally responsible for mitochondrial degradation. We report that giant mitochondria accumulating in cultured rat myoblasts due to inhibition of autophagy have low inner membrane potential and do not fuse with each other or with normal mitochondria. In addition to the low inner mitochondrial membrane potential in giant mitochondria, the quantity of the OPA1 mitochondrial fusion protein in these mitochondria was low, but the abundance of mitofusin-2 (Mfn2) remained unchanged. The combination of these factors may explain the lack of mitochondrial fusion in giant mitochondria and imply that the dysfunctional giant mitochondria cannot restore their function by fusing and exchanging their contents with fully functional mitochondria. These findings have important implications for understanding the mechanisms of accumulation of age-related mitochondrial damage in postmitotic cells. © 2007 Elsevier Inc. All rights reserved.

  • 9.
    Neuzil, Jiri
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Weber, Tobias
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Weber, Christian
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Vitamin E analogues as inducers of apoptosis: implications for their potential anti-neoplastic role2001In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 6, p. 143-151Article in journal (Refereed)
  • 10. Quinn, Carmel M.
    et al.
    Kågedal, Katarina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Stroikin, Yuri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Jessup, Wendy
    Garner, B
    Induction of fibroblast apolipoprotein E expression during apoptosis, starvation-induced growth arrest and mitosis2004In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 378, no 3, p. 753-761Article in journal (Refereed)
    Abstract [en]

    Apolipoprotein E (apoE) mediates the hepatic clearance of plasma lipoproteins, facilitates cholesterol efflux from macrophages and aids neuronal lipid transport. ApoE is expressed at high levels in hepatocytes, macrophages and astrocytes. In the present study, we identify nuclear and cytosolic pools of apoE in human fibroblasts. Fibroblast apoE mRNA and protein levels were up-regulated during staurosporine-induced apoptosis and this was correlated with increased caspase-3 activity and apoptotic morphological alterations. Because the transcription of apoE and specific pro-apoptotic genes is regulated by the nuclear receptor LXR (liver X receptor) α, we analysed LXRα mRNA expression by quantitative real-time PCR and found it to be increased before apoE mRNA induction. The expression of ABCA1 (ATP-binding cassette transporter A1) mRNA, which is also regulated by LXRα, was increased in parallel with apoE mRNA, indicating that LXRα probably promotes apoE and ABCA1 transcription during apoptosis. Fibroblast apoE levels were increased under conditions of serum-starvation-induced growth arrest and hyperoxia-induced senescence. In both cases, an increased nuclear apoE level was observed, particularly in cells that accumulated lipofuscin. Nuclear apoE was translocated to the cytosol when mitotic nuclear disassembly occurred and this was associated with an increase in total cellular apoE levels. ApoE amino acid sequence analysis indicated several potential sites for phosphorylation. In vivo studies, using 32P-labelling and immunoprecipitation, revealed that fibroblast apoE can be phosphorylated. These studies reveal novel associations and potential roles for apoE in fundamental cellular processes.

  • 11.
    Stroikin, Yuri
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Dalen, Helge
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Brunk, Ulf T.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Terman, Alexei
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Testing the “garbage” accumulation theory of ageing: mitotic activity protects cells from death induced by inhibition of autophagy2005In: Biogerontology, ISSN 1389-5729, Vol. 6, no 1, p. 39-47Article in journal (Refereed)
    Abstract [en]

    Imperfect autophagic degradation of oxidatively damaged macromolecules and organelles (so-called biological garbage) is considered an important contributor to ageing and consequent death of postmitotic (non-dividing) cells, such as neurons and cardiac myocytes. In contrast, proliferating cells apparently escape senescence by a continuous dilution and repair of damaged structures during division. Postmitotic ageing can be mimicked and studied in cultures of potentially dividing cells if their mitotic activity is inhibited. To test the garbage accumulation theory of ageing, we compared survival of density-dependent growth-arrested (confluent) and proliferating human fibroblasts and astrocytes following inhibition of autophagic sequestration with 3-methyladenine (3MA). Exposure of confluent fibroblast cultures to 3MA for two weeks resulted in a significantly increased proportion of dying cells compared to both untreated confluent cultures and dividing cells with 3MA-inhibited autophagy. Similar results were obtained when autophagic degradation was suppressed by the protease inhibitor leupeptin. In 3MA- or leupeptin-exposed cultures, dying cells were overloaded with undegraded autofluorescent material. The results support a key role of biological lysosomal garbage accumulation in the triggering of ageing and death of postmitotic cells, as well as the anti-ageing role of cell division.

  • 12.
    Stroikin, Yuri
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Dalen, Helge
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Lööf, Sara
    Terman, Alexei
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences.
    Inhibition of autophagy with 3-methyladenine results in impaired turnover of lysosomes and accumulation of lipofuscin-like material2004In: European journal of cell biology, ISSN 0171-9335, Vol. 83, no 10, p. 583-590Article in journal (Refereed)
    Abstract [en]

    Autophagy (which includes macro-, micro-, and chaperone-mediated autophagy) is an important biological mechanism for degradation of damaged/obsolete macromolecules and organelles. Ageing non-dividing cells, however, progressively accumulate oxidised proteins, defective organelles and intralysosomal lipofuscin inclusions, suggesting inherent insufficiency of autophagy. To learn more about the role of macroautophagy in the turnover of organelles and lipofuscin formation, we inhibited autophagic sequestration with 3-methyladenine (3 MA) in growth-arrested human fibroblasts, a classical model of cellular ageing. Such treatment resulted in a dramatic accumulation of altered lysosomes, displaying lipofuscin-like autofluorescence, as well as in a moderate increase of mitochondria with lowered membrane potential. The size of the late endosomal compartment appeared not to be significantly altered following 3 MA exposure. The accumulation of lipofuscin-like material was enhanced when 3 MA administration was combined with hyperoxia. The findings suggest that macroautophagy is essential for normal turnover of lysosomes. This notion is supported by reports in the literature of lysosomal membrane proteins inside lysosomes and/or late endosomes, as well as lysosomes with active hydrolases within autophagosomes following vinblastine-induced block of fusion between lysosomes and autophagosomes. The data also suggest that specific components of lysosomes, such as membranes and proteins, may be direct sources of lipofuscin.

  • 13.
    Sundelin, Staffan
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Ophthalmology. Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Terman, Alexei
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells2002In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 110, no 6, p. 481-489Article in journal (Refereed)
    Abstract [en]

    Although relatively rare, retinopathy based on a disturbed metabolism of the retinal pigment epithelium (RPE), with ensuing degeneration of photoreceptors, is a known complication of treatment with the 4-aminoquinolones, chloroquine (CQ) and hydroxychloroquine (HCQ), in autoimmune diseases. The reported frequency of retinopathy, however, is much lower for HCQ than for CQ (less than 0.08% versus 1–2%). To test whether the difference in toxicity between the two lysosomotropic drugs is related to different lysosomal influence, we exposed confluent RPE cell cultures to CQ or HCQ for 2 weeks. To induce lipofuscin (LF) formation, known to be accelerated by increased lysosomal pH and intra-lysosomal oxidation during degradation of auto-/heterophagocytosed material, such treatment was combined with feeding of cells with photoreceptor outer segments (POS) and hyperoxia (40% ambient oxygen). HCQ was found to be a less potent enhancer of lipofuscinogenesis compared to CQ, apparently due to its less effective inhibition of lysosomal degradative capacity (evaluated by vital staining of lysosomes with Lyso Tracker Red, and periodic acid-Schiff reaction). This conclusion is supported by the fact that NH4Cl, a non-fluorescent substance which acts similarly to 4-aminoquinolones, induced an increase in LF fluorescence paralleled by increased periodic acid-Schiff reactivity of RPE cells.

  • 14.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Catabolic insufficiency and aging2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1067, p. 27-36Article in journal (Refereed)
  • 15.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Garbage catastrophe theory of aging: Imperfect removal of oxidative damage?2001In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 6, no 1, p. 15-26Article in journal (Refereed)
    Abstract [en]

    Increasing evidence suggests an important role of oxidant-induced damage in the progress of senescent changes, providing support for the free radical theory of aging proposed by Harman in 1956. However, considering that biological organisms continuously renew their structures, it is not clear why oxidative damage should accumulate with age. No strong evidence has been provided in favor of the concept of aging as an accumulation of synthetic errors (e.g. Orgel's 'error-catastrophe' theory and the somatic mutation theory). Rather, we believe that the process of aging may derive from imperfect clearance of oxidatively damaged, relatively indigestible material, the accumulation of which further hinders cellular catabolic and anabolic functions. From this perspective, it might be predicted that: (i) suppression of oxidative damage would enhance longevity, (ii) accumulation of incompletely digested material (e.g. lipofuscin pigment) would interfere with cellular functions and increase probability of death, (iii) rejuvenation during reproduction is mainly provided by dilution of undigested material associated with intensive growth of the developing organism, and (iv) age-related damage starts to accumulate substantially when development is complete, and mainly affects postmitotic cells and extracellular matrix, not proliferating cells. There is abundant support for all these predictions.

  • 16.
    Terman, Alexei
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Mechanisms of lipofuscin/ceroid accumulation and its impact on the function of the lysosomal system1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The accumulation of lipofuscin - an electron-dense, autofluorescent, polymeric, intralysosomal substance - is a recognized hallmark of aging postmitotic cells. Ceroid- a substance very close, or perhaps even identical, to lipofuscin - is a characteristic of various pathological processes, such as lysosomal storage diseases, malnutrition, atherosclerosis, oxidative stress, ionizing radiation, etc. Although the mechanisms of lipofuscin formation are now rather well understood (Brunk et al., 1992), what causes it to accumulate within aging postmitotic cells (namely, the role of its possibly impaired degradation/exocytosis) is still disputed. Moreover, little is known about whether lipofuscin accumulation interferes with normal cellular functions, perhaps it even promotes cell death and age-associated pathologies. The role, if any, of ceroid accumulation in the pathogenesis of many diseases also is not clear.

    To gain a better insight into the mechanisms of lipofuscin/ceroid accumulation, and to test whether this accumulation has any negative impact on cellular functions, especially on the autophagocytotic process, we decided to study: (l) the role of oxidative stress (normobaric hyperoxia) and/or lysosomal protease inhibition (leupeptin treatment) in lipofuscin/ceroid accumulation in cultured AG-1518 human fibroblasts and neonatal rat cardiac myocytes; (2) the fate of formed lipofuscin/ceroid after the cessation of oxidative stress and/or protease inhibition; (3) the possible reversal of lipofuscin/ceroid accumulation in vitro with an anti-aging drug centrophenoxine; (4) the survival of lipofuscin/ceroid-loaded fibroblasts under amino acid starvation; (5) the effect of lipofuscin/ceroid accumulation on autophagocytosis and intralysosomal degradation; and (6) the sensitivity of lipofuscin/ceroid-loaded fibroblasts to oxidative stress.

    We have shown that: (1) both oxidative stress and lysosomal protease inhibition accelerated lipofuscin/ceroid formation, however the effects of these two factors increased dramatically when they acted concurrently; (2) protease-inhibition by itself does not lead to lipofuscin/ceroid formation, but rather allows the prolonged time needed for oxidative modification of autophagocytosed material; (3) lipofuscin/ceroid inclusions formed due to oxidative stress and protease inhibition do not disappear either after returning the cultured cells to normal conditions, during amino acid starvation, or under the influence of centrophenoxine; (4) lipofuscin/ceroid-loaded cells exposed to amino acid starvation show decreased survival time and diminished autophagocytosis; (5) exposure of fibroblasts with various amounts of lipofuscin/ceroid to naphthazarin (a redox cycling quinone producing 0 2 ·-and H20 2) results in selective survival of cells with lower quantities of the pigment; and (6) lipofuscin/ceroid-rich cells have an expanded lysosomal compartment with increased amounts of cathepsin D.

    The results suggest that: (i) lipofuscin/ceroid forms within secondary lysosomes due to oxidative damage of autophagocytosed material resulting in cross-linking of protein residues by aldehydes formed from decomposed peroxidized unsaturated lipids; (ii) lipofuscin/ceroid is not substantially eliminated from non-dividing cells by degradation or exocytosis, which explains the progressive accumulation of lipofuscin in postmitotic cells with age; and (iii) a heavy lipofuscin/ceroid loading of cells interferes with normal lysosomal functions by making them less able to autophagocytose and more sensitive to oxidative stress, conceivably due to increased amounts of lysosomal enzymes (potential mediators of oxidative damage) and/or due to a possible catalyzing role of lipofuscin/ceroid-associated iron.

  • 17.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Abrahamsson, N.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Ceroid/lipofuscin-loaded human fibroblasts show increased susceptibility to oxidative stress.1999In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 34, p. 755-770Article in journal (Refereed)
  • 18.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Aging and lysosomal degradation of cellular constituents2003In: Aging at the molecular level / [ed] Thomas von Zglinicki, Linköping: Linköpings universitet , 2003, p. 233-242Chapter in book (Other academic)
    Abstract [en]

    The essential cause of aging is molecular damage that slowly overwhelms cellular and organismic defense, repair and maintenance systems. Sophisticated research has transformed this idea from a credible hypothesis to accepted knowledge. This work examines the key elements in this transformation. It is useful for students and researchers

  • 19.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Aging as a catabolic malfunction2004In: International Journal of Biochemistry and Cell Biology, ISSN 1357-2725, E-ISSN 1878-5875, Vol. 36, no 12, p. 2365-2375Article, review/survey (Refereed)
    Abstract [en]

    Cellular degradative processes, which include lysosomal (autophagic) and proteasomal degradation, as well as catabolism of proteins by cytosolic and mitochondrial proteases, provide for a continuous turnover of cellular components, such as damaged or obsolete biomolecules and organelles. Inherent insufficiency of these degradative processes results in progressive accumulation within long-lived postmitotic cells of biological 'garbage' (waste material), such as various oxidized proteins, functionally effete mitochondria, and lipofuscin (age pigment), an intralysosomal, polymeric, undegradable material. There is increasing evidence that lipofuscin hampers lysosomal degradative capacity, thus promoting the aggravation of accumulated damage at old age. Being rich in redox-active iron, lipofuscin granules also may exacerbate oxidative stress levels in senescent cells. Thus, increasing the efficiency of cellular degradative pathways and preventing involvement of iron in oxidant-induced lysosomal and cellular damage may be potential strategies for anti-aging interventions. © 2004 Elsevier Ltd. All rights reserved.

  • 20.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Aging as a catabolic malfunction2004In: International Journal of Biochemistry and Cell Biology, ISSN 1357-2725, E-ISSN 1878-5875, Vol. 36, p. 2365-2375Article in journal (Refereed)
  • 21.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Autophagy in cardiac myocyte homeostasis, aging, and pathology2005In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 68, no 3, p. 355-365Article in journal (Refereed)
    Abstract [en]

    Autophagy, an intralysosomal degradation of cells' own constituents that includes macro-, micro-, and chaperone-mediated autophagy, plays an important role in the renewal of cardiac myocytes. This cell type is represented by long-lived postmitotic cells with very poor (if any) replacement through differentiation of stem cells. Macroautophagy, the most universal form of autophagy, is responsible for the degradation of various macromolecules and organelles including mitochondria and is activated in response to stress, promoting cell survival. This process is also involved in programmed cell death when injury is irreversible. Even under normal conditions, autophagy is somewhat imperfect, underlying gradual accumulation of defective mitochondria and lipofuscin granules within aging cardiac myocytes. Autophagy is involved in the most important cardiac pathologies including myocardial hypertrophy, cardiomyopathies, and ischemic heart disease, a fact that has led to increasing attention to this process. © 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

  • 22.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Is aging the price for memory?2005In: Biogerontology (Dordrecht), ISSN 1389-5729, E-ISSN 1573-6768, Vol. 6, no 3, p. 205-210Article in journal (Other academic)
    Abstract [en]

    Aging (senescence) is apparent in animals that possess long-lived postmitotic cells but is negligible in primitive species, such as hydras and other Cnidarians, all of whose cells are constantly renewed by cell division. This repetitive mitotic activity precludes the progressive intracellular accumulation of damaged biomolecules and organelles, which are obvious concomitants of aging in neurons and other long-lived cells of higher animals. We assume that the development of long-lived postmitotic cells, now found in the overwhelming majority of species, represented a useful evolutionary change. Probably, of particular importance was the evolution of long-lived neurons, which are required for long-term memory. However, the appearance of long-lived postmitotic cells not only increased fitness, but also gave rise to the aging process.

  • 23.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Is lipofuscin eliminated from cells?1999In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 40, p. 2463-2464Article in journal (Refereed)
  • 24.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Lipofuscin2004In: International Journal of Biochemistry and Cell Biology, ISSN 1357-2725, E-ISSN 1878-5875, Vol. 36, no 8, p. 1400-1404Article, review/survey (Refereed)
    Abstract [en]

    Over time, postmitotic cells accumulate a non-degradable intralysosomal substance, lipofuscin, which forms due to iron-catalyzed oxidation/ polymerization of protein and lipid residues. Lipofuscin is often considered a hallmark of aging, showing an accumulation rate that inversely correlates with longevity. There is an emerging impression that lipofuscin, although still typically considered a harmless wear-and-tear product, may have multiple negative effects. By interfering with the important autophagic process, by which most worn out cellular components are degraded, it may prevent cellular renewal and advance the accumulation of damaged cellular constituents. Due to binding of transition metals, such as iron and copper, lipofuscin also seems to sensitize lysosomes and cells to oxidative stress. Of importance for the pathogenesis of age-related macular degeneration, lipofuscin deposition interferes with the phagocytic activity of retinal pigment epithelial cells and also sensitizes their lysosomes to blue light. © 2003 Published by Elsevier Ltd.

  • 25.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Lipofuscin2004In: International Journal of Biochemistry and Cell Biology, ISSN 1357-2725, E-ISSN 1878-5875, Vol. 36, p. 1400-1404Article in journal (Refereed)
  • 26.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Myocyte aging and mitochondrial turnover2004In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 39, no 5, p. 701-705Article, review/survey (Refereed)
    Abstract [en]

    Cardiac myocytes, skeletal muscle fibers, and other long-lived postmitotic cells show dramatic age-related alterations that mainly affect mitochondria and the lysosomal compartment. Mitochondria are primary sites of reactive oxygen species formation that causes progressive damage to mitochondrial DNA and proteins in parallel to intralysosomal lipofuscin accumulation. There is amassing evidence that several various mechanisms may contribute to age-related accumulation of damaged mitochondria following initial oxidative injury. Such mechanisms may include clonal expansion of defective mitochondria, decreased propensity of altered mitochondria to become autophagocytosed (due to mitochondrial enlargement or decreased membrane damage associated with weakened respiration), suppressed autophagy because of heavy lipofuscin loading of lysosomes, and decreased efficiency of Lon protease. © 2004 Elsevier Inc. All rights reserved.

  • 27.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Myocyte aging and mitochondrial turnover2004In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 39, p. 701-705Article in journal (Refereed)
  • 28.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Oxidative stress, accumulation of biological 'garbage', and aging2006In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 8, no 1-2, p. 197-204Article in journal (Refereed)
    Abstract [en]

    Normal metabolism is associated with unavoidable mild oxidative stress resulting in biomolecular damage that cannot be totally repaired or removed by cellular degradative systems, including lysosomes, proteasomes, and cytosolic and mitochondrial proteases. Consequently, irreversibly damaged and functionally defective structures (biological 'garbage') accumulate within long-lived postmitotic cells, such as cardiac myocytes and neurons, leading to progressive loss of adaptability and increased probability of death and characterizing a process called aging, or senescence. Intralysosomal 'garbage' is represented by lipofuscin (age pigment), an undegradable autophagocytosed material, while extralysosomal 'garbage' involves oxidatively modified cytosolic proteins, altered biomembranes, defective mitochondria and other organelles. In aged postmitotic cells, heavily lipofuscin-loaded lysosomes perform poorly, resulting in the enhanced accumulation of defective mitochondria, which in turn produce more reactive oxygen species causing additional damage (the mitochondrial- lysosomal axis theory). Potential anti-aging strategies may involve not only overall reduction of oxidative stress, but also the use of intralysosomal iron chelators hampering Fenton-type chemistry as well as the stimulation of cellular degradative systems. © Mary Ann Liebert, Inc.

  • 29.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    The aging myocardium: Roles of mitochondrial damage and lysosomal degradation2005In: Heart, Lung and Circulation, ISSN 1443-9506, E-ISSN 1444-2892, Vol. 14, no 2, p. 107-114Article in journal (Refereed)
    Abstract [en]

    Myocardial aging, leading to circulatory dysfunction, complicates numerous pathologies and is an important contributor to overall mortality at old age. In cardiac myocytes, mitochondria and lysosomes suffer remarkable age-related alterations. Mitochondrial changes include structural disorganization and enlargement, while lysosomes, which are responsible for autophagic turnover of mitochondria, accumulate lipofuscin (age pigment), a polymeric, autofluorescent, undegradable material. These changes are caused by continuous physiological oxidative stress, and they advance with age because the cellular turnover machinery is inherently imperfect. Several mechanisms contribute to age-related accumulation of damaged mitochondria following initial oxidative injury. Such mechanisms may include clonal expansion of defective mitochondria, decreased propensity of altered mitochondria to become autophagocytosed (due to mitochondrial enlargement or decreased membrane damage associated with weakened respiration), suppressed autophagy because of heavy lipofuscin loading of lysosomes, and decreased efficiency of Lon and AAA proteases. Because lipofuscin-laden lysosomes still receive newly synthesized lysosomal enzymes, even though they fail to degrade the pigment, the cells become in short supply of lysosomal hydrolases for functional autophagy, further limiting mitochondrial turnover. This interrelated mitochondrial and lysosomal damage eventually results in functional failure and death of cardiac myocytes. © 2005 Published by Elsevier Inc on behalf of Australasian Society of Caridac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand.

  • 30.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    The effect of Polbax extract on lipofuscin accumulation in cultured neonatal rat cardiac myocytes2002In: Phytotherapy Research, ISSN 0951-418X, E-ISSN 1099-1573, Vol. 16, no 2, p. 180-182Article in journal (Refereed)
    Abstract [en]

    Polbax«, a water-soluble extract of fresh pollen grains and pistils, was tested for its ability to influence the accumulation of lipofuscin (age pigment) in cultured neonatal rat cardiac myocytes. Exposure for 3 weeks to Polbax at concentrations of 0.1, 1.0 or 10 mg/L decreased lipofuscin accumulation morphometrically assayed using laser scanning microscopy images (green excitation light) of formaldehyde-fixed cells, by 24%, 41% or 43%, respectively. Based on the knowledge that oxidative stress and iron-catalysed peroxidation play an important role in lipofuscinogenesis, we suggest that Polbax may slow lipofuscin formation due to antioxidant activities, perhaps involving intralysosomal dismutation of superoxide produced by autophagocytosed mitochondria and/or iron-chelation.

  • 31.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Dalen, H
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Ceroid/lipofuscin-loaded human fibroblasts show decreased survival time and diminished autophagocytosis under amino acid starvation.1999In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 34, p. 943-957Article in journal (Refereed)
  • 32.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Dalen, Helge
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mitochondrial recycling and aging of cardiac myocytes: The role of autophagocytosis2003In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 38, no 8, p. 863-876Article in journal (Refereed)
    Abstract [en]

    The mechanisms of mitochondrial alterations in aged post-mitotic cells, including formation of so-called 'giant' mitochondria, are poorly understood. To test whether these large mitochondria might appear due to imperfect autophagic mitochondrial turnover, we inhibited autophagocytosis in cultured neonatal rat cardiac myocytes with 3-methyladenine. This resulted in abnormal accumulation of mitochondria within myocytes, loss of contractility, and reduced survival time in culture. Unlike normal aging, which is associated with slow accumulation of predominantly large defective mitochondria, pharmacological inhibition of autophagy caused only moderate accumulation of large (senescent-like) mitochondria but dramatically enhanced the numbers of small mitochondria, probably reflecting their normally more rapid turnover. Furthermore, the 3-methyladenine-induced accumulation of large mitochondria was irreversible, while small mitochondria gradually decreased in number after withdrawal of the drug. We, therefore, tentatively conclude that large mitochondria selectively accumulate in aging post-mitotic cells because they are poorly autophagocytosed. Mitochondrial enlargement may result from impaired fission, a possibility supported by depressed DNA synthesis in large mitochondria. Nevertheless, enlarged mitochondria retained immunoreactivity for cytochrome c oxidase subunit 1, implying that mitochondrial genes remain active in defective mitochondria. Our findings suggest that imperfect autophagic recycling of these critical organelles may underlie the progressive mitochondrial damage, which characterizes aging post-mitotic cells.

  • 33.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Dalen, Helge
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Brunka, UT
    Aging of cardiac myocytes in culture - Oxidative stress, lipofuscin accumulation, and mitochondrial turnover2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1019, p. 70-77Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is believed to be an important contributor to aging, mainly affecting long-lived postmitotic cells such as cardiac myocytes and neurons. Aging cells accumulate functionally effete, often mutant and enlarged mitochondria, as well as an intralysosomal undegradable pigment, lipofuscin. To provide better insight into the role of oxidative stress, mitochondrial damage, and lipofuscinogenesis in postmitotic aging, we studied the relationship between these parameters in cultured neonatal rat cardiac myocytes. It was found that the content of lipofuscin, which varied drastically between cells, positively correlated with mitochondrial damage (evaluated by decreased innermembrane potential), as well as with the production of reactive oxygen species. These results suggest that both lipofuscin accumulation and mitochondrial damage have common underlying mechanisms, likely including imperfect autophagy and ensuing lysosomal degradation of oxidatively damaged mitochondria and other organelles. Increased size of mitochondria (possibly resulting from impaired fission due to oxidative damage to mitochondrial DNA, membranes, and proteins) also may interfere with mitochondrial turnover, leading to the appearance of so-called "giant" mitochondria. This assumption is based on our observation that pharmacological inhibition of autophagy with 3-methyladenine induced only moderate accumulation of large (senescent-like) mitochondria but drastically increased numbers of small, apparently normal mitochondria, reflecting their rapid turnover and suggesting that enlarged mitochondria are poorly autophagocytosed. Overall, our findings emphasize the importance of mitochondrial turnover in postmitotic aging and provide further support for the mitochondrial-lysosomal axis theory of aging.

  • 34.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Autophagy, organelles and ageing2007In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 211, no 2, p. 134-143Article, review/survey (Refereed)
    Abstract [en]

    As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy and other degradative systems, long-lived postmitotic cells, such as cardiac myocytes, neurons and retinal pigment epithelial cells, progressively accumulate biological 'garbage' ('waste' materials). The latter include lipofuscin (a non-degradable intralysosomal polymeric substance), defective mitochondria and other organelles, and aberrant proteins, often forming aggregates (aggresomes). An interaction between senescent lipofuscin-loaded lysosomes and mitochondria seems to play a pivotal role in the progress of cellular ageing. Lipofuscin deposition hampers autophagic mitochondrial turnover, promoting the accumulation of senescent mitochondria, which are deficient in ATP production but produce increased amounts of reactive oxygen species. Increased oxidative stress, in turn, further enhances damage to both mitochondria and lysosomes, thus diminishing adaptability, triggering mitochondrial and lysosomal pro-apoptotic pathways, and culminating in cell death. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • 35.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics.
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Mitochondrial damage and intralysosomal degradation in cellular aging2006In: Molecular Aspects of Medicine, ISSN 0098-2997, E-ISSN 1872-9452, Vol. 27, no 5-6, p. 471-482Article in journal (Refereed)
    Abstract [en]

    Normal mitochondrial respiration is associated with a continuous production of superoxide and hydrogen peroxide, inevitably resulting in minor macromolecular damage. Damaged cellular components are not completely turned over by autophagy and other cellular repair systems, leading to a progressive age-related accumulation of biological "garbage" material, such as defective mitochondria, cytoplasmic protein aggregates and an intralysosomal undegradable material, lipofuscin. These changes primarily affect neurons, cardiac myocytes and other long-lived postmitotic cells that neither dilute this "garbage" by mitotic activity, nor are replaced by newly differentiated cells. Defective mitochondria are insufficient in ATP production and often generate increased amounts of reactive oxygen species, further enhancing oxidative stress. Lipofuscin-loaded lysosomes, in turn, poorly turn over mitochondria that gradually leads to the overload of long-lived postmitotic cells with "garbage" material, decreased adaptability and eventual cell death. © 2006 Elsevier Ltd. All rights reserved.

  • 36.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics.
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    The lysosomal-mitochondrial axis theory of postmitotic aging and cell death2006In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 163, no 1-2, p. 29-37Article in journal (Refereed)
    Abstract [en]

    Aging (senescence) is characterized by a progressive accumulation of macromolecular damage, supposedly due to a continuous minor oxidative stress associated with mitochondrial respiration. Aging mainly affects long-lived postmitotic cells, such as neurons and cardiac myocytes, which neither divide and dilute damaged structures, nor are replaced by newly differentiated cells. Because of inherent imperfect lysosomal degradation (autophagy) and other self-repair mechanisms, damaged structures (biological "garbage") progressively accumulate within such cells, both extra- and intralysosomally. Defective mitochondria and aggregated proteins are the most typical forms of extralysosomal "garbage", while lipofuscin that forms due to iron-catalyzed oxidation of autophagocytosed or heterophagocytosed material, represents intralysosomal "garbage". Based on findings that autophagy is diminished in lipofuscin-loaded cells and that cellular lipofuscin content positively correlates with oxidative stress and mitochondrial damage, we have proposed the mitochondrial-lysosomal axis theory of aging, according to which mitochondrial turnover progressively declines with age, resulting in decreased ATP production and increased oxidative damage. Due to autophagy of ferruginous material, lysosomes contain a pool of redox-active iron, which makes these organelles particularly susceptible to oxidative damage. Oxidant-mediated destabilization of lysosomal membranes releases hydrolytic enzymes to the cytosol, eventuating in cell death (either apoptotic or necrotic depending on the magnitude of the insult), while chelation of the intralysosomal pool of redox-active iron prevents these effects. In relation to the onset of oxidant-induced apoptosis, but after the initiating lysosomal rupture, cytochrome c is released from mitochondria and caspases are activated. Mitochondrial damage follows the release of lysosomal hydrolases, which may act either directly or indirectly, through activation of phospholipases or pro-apoptotic proteins such as Bid. Additional lysosomal rupture seems to be a consequence of a transient oxidative stress of mitochondrial origin that follows the attack by lysosomal hydrolases and/or phospholipases, creating an amplifying loop system. © 2006 Elsevier Ireland Ltd. All rights reserved.

  • 37.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Kurz, Tino
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Lysosomal labilization2006In: IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology, ISSN 1521-6543, E-ISSN 1521-6551, Vol. 58, no 9, p. 531-539Article, review/survey (Refereed)
    Abstract [en]

    The lysosomal compartment is the place for cellular degradation of endocytosed and autophagocytosed material and a center for normal turnover of organelles as well as most long-lived proteins. Lysosomes were long considered stable structures that broke and released their many hydrolytic enzymes only following necrotic cell death. It is now realized that lysosomes instead are quite vulnerable, although in a heterogeneous way. Their exposure to a number of events, such as oxidative stress, lysosomotropic detergents and aldhydes, as well as overexpression of the p53 protein, causes time-and-dose-dependent lysosomal rupture that is followed by apoptosis or necrosis. Partial lysosomal rupture has often been found to be an early upstream event in apoptosis, while necrosis results from fulminant lysosomal rupture. Consequently, factors influencing the stability of lysosomes, for instance their content of labile and redox-active iron, seem to be essential for the survival of cells. © 2006 IUBMB.

  • 38.
    Terman, Alexei
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Laboratory of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Kurz, Tino
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Gustafsson, Bertil
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Cytology. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    The involvement of lysosomes in myocardial aging and disease2008In: Current Cardiology Reviews, ISSN 1573-403X, Vol. 4, no 2, p. 107-115Article, review/survey (Refereed)
    Abstract [en]

    The myocardium is mainly composed of long-lived postmitotic cells with, if there is any at all, a very low rate of replacement through the division and differentiation of stem cells. As a consequence, cardiac myocytes gradually undergo pronounced age-related alterations which, furthermore, occur at a rate that inversely correlates with the longevity of species. Basically, these alterations represent the accumulation of structures that have been damaged by oxidation and that are useless and often harmful. These structures (so-called 'waste' materials), include defective mitochondria, aberrant cytosolic proteins, often in aggregated form, and lipofuscin, which is an intralysosomal undegradable polymeric substance. The accumulation of 'waste' reflects the insufficient capacity for autophagy of the lysosomal compartment, as well, as the less than perfect functioning of proteasomes, calpains and other cellular digestive systems. Senescent mitochondria are usually enlarged, show reduced potential over their inner membrane, are deficient in ATP production, and often produce increased amounts of reactive oxygen species. The turnover of damaged cellular structures is hindered by an increased lipofuscin loading of the lysosomal compartment. This particularly restricts the autophagic turnover of enlarged, defective mitochondria, by diverting the flow of lysosomal hydrolases from autophagic vacuoles to lipofuscin-loaded lysosomes where the enzymes are lost, since lipofuscin is not degradable by lysosomal hydrolases. As a consequence, aged lipofuscin-rich cardiac myocytes become overloaded with damaged mitochondria, leading to increased oxidative stress, apoptotic cell death, and the gradual development of heart failure. Defective lysosomal function also underlies myocardial degeneration in various lysosomal storage diseases, while other forms of cardiomyopathies develop due to mitochondrial DNA mutations, resulting in an accumulation of abnormal mitochondria that are not properly eliminated by autophagy. The degradation of iron-saturated ferritin in lysosomes mediates myocardial injury in hemochromatosis, an acquired or hereditary disease associated with iron overload. Lysosomes then become sensitized to oxidative stress by the overload of low mass, redox-active iron that accumulates when iron-saturated ferritin is degraded following autophagy. Lysosomal destabilization is of importance in the induction and/or execution of programmed cell death (either classical apoptotic or autophagic), which is a common manifestation of myocardial aging and a variety of cardiac pathologies. © 2008 Bentham Science Publishers Ltd.

  • 39.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Kågedal, Katarina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Öllinger, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Decreased apoptotic response of inclusion-cell disease fibroblasts: A consequence of lysosomal enzyme missorting?2002In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 274, no 1Article in journal (Refereed)
    Abstract [en]

    To better understand the role of lysosomes in apoptosis, we compared the responses to apoptotic stimuli of normal fibroblasts with those of inclusion cells (I-cells), i.e., fibroblasts with impaired function of lysosomal enzymes due to their missorting and ensuing nonlysosomal localization. Although both cell types did undergo apoptosis when exposed to the lysosomotropic detergent MSDH, the redox-cycling quinone naphthazarin, or the protein kinase inhibitor staurosporine, I-cells exerted a markedly decreased response to these agonists than did normal fibroblasts. Furthermore, leupeptin and pepstatin A (inhibitors of cysteine and aspartic proteases, respectively) suppressed staurosporine-induced apoptosis of normal fibroblasts, whereas survival of I-cells was unaffected. These findings give further support for the involvement of lysosomal enzymes in apoptosis and suggest I-cells as a suitable model for studying the role of lysosomes in programmed cell death.

  • 40.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Sandberg, Sandra
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Proteasome inhibition enhances lipofuscin formation2002In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 973, p. 309-312Article in journal (Refereed)
    Abstract [en]

    Lipofuscin, a hallmark of aged nondividing cells, is an undegradable autofluorescent intralysosomal substance composed essentially of oxidized, cross-linked proteins. To test whether impaired activity of proteasomes-which, along with lysosomes, belong to major cellular proteolytic systems-may contribute to lipofuscinogenesis, we exposed growth-arrested human fibroblasts to subapoptotic doses (2 and 5 nM) of a highly specific proteasome inhibitor, MG-262. This resulted in accelerated lipofuscin accumulation (especially when MG-262 exposure was combined with mild hyperoxia cultivation at 40% ambient oxygen versus 8% for controls), and enhanced immunostaining for ubiquitin, reflecting accumulation of modified cytosolic proteins subjected for degradation, and cathepsin L, reflecting enlargement of the lysosomal compartment. These data suggest that insufficient proteasomal function may contribute to lipofuscinogenesis by a compensatory increase in the amount of proteins that are difrected for lysosomal degradation. The findings may be helpful for the understanding of cellular aging as well as diseases associated with intralysosomal accumulation of undegradable material.

  • 41.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Welander, M.
    Centrophenoxine slows down but does not reverse, lipofuscin accumulation in cultured cells.1999In: Journal of Anti-Aging Medicine, ISSN 1094-5458, E-ISSN 1557-8984, Vol. 2, p. 265-273Article in journal (Refereed)
  • 42.
    Wearden, ME
    et al.
    Baylor Coll Med, Houston, TX 77030 USA Linkoping Univ Hosp, S-58185 Linkoping, Sweden.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mitochondria: Potential importance in hyperoxic lung injury2000In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 47, no 4, p. 2244-Conference paper (Other academic)
  • 43. Weber, A
    et al.
    Dalen, Helge
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Andera, L
    Nègre-Salvayre, A
    Augé, N
    Sticha, M
    Loret, A
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Witting, PK
    Higuchi, M
    Plasilova, M
    Zivny, J
    Gellert, N
    Weber, C
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Mitochondria play a central role in apoptosis induced by a-tocopheryl succinate, an agent with antineoplastic activity: Comparison with receptor-mediated pro-apoptotic signaling2003In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 42, no 14, p. 4277-4291Article in journal (Refereed)
    Abstract [en]

    a-Tocopheryl succinate (a-TOS) is a semisynthetic vitamin E analogue with high pro-apoptotic and anti-neoplastic activity [Weber, T et al. (2002) Clin. Cancer Res. 8, 863-869]. Previous studies suggested that it acts through destabilization of subcellular organelles, including mitochondria, but compelling evidence is missing. Cells treated with a-TOS showed altered mitochondrial structure, generation of free radicals, activation of the sphingomyelin cycle, relocalization of cytochrome c and Smac/Diablo, and activation of multiple caspases. A pan-caspase inhibitor suppressed caspase-3 and -6 activation and phosphatidyl serine externalization, but not decrease of mitochondrial membrane potential or generation of radicals. For a-TOS, but not Fas or TRAIL, apoptosis was suppressed by caspase-9 inhibition, while TRAIL- and Fas-resistant cells overexpressing cFLIP or CrmA were susceptible to a-TOS. The central role of mitochondria was confirmed by resistance of mtDNA-deficient cells to a-TOS, by regulation of a-TOS apoptosis by Bcl-2 family members, and by anti-apoptotic activity of mitochondrially targeted radical scavengers. Co-treatment with a-TOS and anti-Fas IgM showed their cooperative effect, probably by signaling via different, convergent pathways. These data provide an insight into the molecular mechanism, by which a-TOS kills malignant cells, and advocate its testing as a potential anticancer agent or adjuvant.

  • 44. Weber, Tobias
    et al.
    Lu, Min
    Andera, Ladislav
    Lahm, Harald
    Gellert, Nina
    Fariss, Marc W
    Korinek, Vladimir
    Sattler, Wolfgang
    Ucker, David S
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Schröder, Andreas
    Erl, Wolfgang
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Coffey, Robert
    Weber, Christian
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Vitamin E succinate is a potent novel anti-neoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo2002In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 8, p. 863-869Article in journal (Refereed)
  • 45.
    Zheng, Lin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Dehvari, Nodi
    Karolinska Institutet, Stockholm.
    Benedikz, Eirikur
    Karolinska Institutet, Stockholm.
    Cowburn, Richard
    AstraZeneca R&D.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Terman, Alexei
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis2009In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 46, no 3, p. 422-429Article in journal (Refereed)
    Abstract [en]

    There is increasing evidence for the toxicity of intracellular amyloid beta-protein (A beta) to neurons and the involvement of lysosomes in this process in Alzheimer disease (AD). We have recently shown that oxidative stress, a recognized determinant of AD. enhances macroautophagy and leads to intralysosomal accumulation of A beta in Cultured neuroblastoma cells. We hypothesized that oxidative stress promotes AD by stimulating macroautophagy of A that further may induce cell death by destabilizing lysosomal membranes. To investigate such possibility, we compared the effects of hyperoxia (40% ambient oxygen) in cultured HEK293 cells that were transfected with an empty vector (Vector), wild-type APP (APPwt), or Swedish mutant APP (APPswe). Exposure to hyperoxia for 5 days increased the number of cells with A beta-containing lysosomes, as well as the number of apoptotic cells, compared to normoxic conditions. The rate of apoptosis in all three cell lines demonstrated dependence on intralysosomal A beta content (Vector<APPwt<APPswe). Furthermore, the degree of apoptosis was positively correlated with lysosomal membrane permeabilization, whereas inhibitors Of macroautophagy and lysosomal function decreased oxidant-induced apoptosis and diminished the differences in apoptotic response between different cell lines. These results suggest that oxidative stress can induce neuronal death through macroautophagy of A beta and consequent lysosomal membrane permeabilization, which may help explain the mechanisms behind neuronal loss in AD.

  • 46.
    Zheng, Lin
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Marcusson, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Oxidative stress and Alzheimer disease - The autophagy connection?2006In: AUTOPHAGY, ISSN 1554-8627, Vol. 2, no 2, p. 143-145Article in journal (Refereed)
    Abstract [en]

    Intraneuronal accumulation of amyloid beta-protein (A beta) is believed to be responsible for degeneration and apoptosis of neurons and consequent senile plaque formation in Alzheimer disease (AD), the main cause of senile dementia. Oxidative stress, an early determinant of AD, has been recently found to induce intralysosomal A beta accumulation in cultured differentiated neuroblastoma cells through activation of macroautophogy. Because A beta is known to destabilize lysosomal membranes, potentially resulting in apoptotic cell death, this finding suggests the involvement of oxidative stress-induced macroautophagy in the pathogenesis of AD.

  • 47.
    Zheng, Lin
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Oto-Rhiono-Laryngology and Head & Neck Surgery. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Jerhammar, Fredrik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Marcusson, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Autophagy of amyloid beta-protein in differentiated neuroblastoma cells exposed to oxidative stress2006In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 394, no 3, p. 184-189Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is considered important for the pathogenesis of Alzheimer disease (AD), which is characterized by the formation of senile plaques rich in amyloid beta-protein (Aβ). Aβ cytotoxicity has been found dependent on lysosomes, which are abundant in AD neurons and are shown to partially co-localize with Aβ. To determine whether oxidative stress has any influence on the relationship between lysosomes and Aβ1-42 (the most toxic form of Aβ), we studied the effect of hyperoxia (40% versus 8% ambient oxygen) on the intracellular localization of Aβ1-42 (assessed by immunocytochemistry) in retinoic acid differentiated SH-SY5Y neuroblastoma cells maintained in serum-free OptiMEM medium. In control cells, Aβ1-42 was mainly localized to small non-lysosomal cytoplasmic granules. Only occasionally Aβ1-42 was found in large (over 1 μm) lysosomal-associated membrane protein 2 positive vacuoles, devoid of the early endosomal marker rab5. These large Aβ1-42-containing lysosomes were not detectable in the presence of serum (known to suppress autophagy), while their number increased dramatically (up to 24-fold) after exposure of cells to hyperoxia during 5 days. Activation of autophagy by hyperoxia was confirmed by transmission electron microscopy. Furthermore, an inhibitor of autophagic sequestration 3-methyladenine prevented the accumulation of Aβ1-42-positive lysosomes due to hyperoxia. In parallel experiments, intralysosomal accumulation of Aβ1-40 following oxidative stress has been found as well. The results suggest that Aβ can be autophagocytosed and its accumulation within neuronal lysosomes is enhanced by oxidative stress. © 2005 Elsevier Ireland Ltd. All rights reserved.

  • 48.
    Zheng, Lin
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Neuroscience and Locomotion, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Jerhammar, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Linköping University, Faculty of Health Sciences.
    Terman, Alexei
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Oxidative Stress Induces Intralysosomal Accumulation of Alzheimer Amyloid β-Protein in Cultured Neuroblastoma Cells2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1067, p. 248-251Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is considered important for the pathogenesis of Alzheimer's disease (AD), which is characterized by the formation of extracellular senile plaques, mainly composed of amyloid β-protein (Aβ). Aβ also accumulates within AD neurons and is believed to exert cellular toxicity through lysosomal labilization. We report that the exposure of human neuroblastoma cells to hyperoxia (40% vs. 8% ambient oxygen) induced the accumulation of large (over 1 μM) Aβ-containing lysosomes, which were not typical of control cells, showing a distinct localization of Aβ and lysosomal markers. An inhibitor of autophagy, 3-methyladenine, suppressed the effect of hyperoxia. The results suggest a link between the involvement of oxidative stress and lysosomes in AD.

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