liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
α-lipoic acid and α-lipoamide prevent oxidant-induced lysosomal rupture and apoptosis
Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
2001 (English)In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 6, no 5, 327-334 p.Article in journal (Refereed) Published
Abstract [en]

α-Lipoic acid (LA) and its corresponding derivative, α-lipoamide (LM), have been described as antioxidants, but the mechanisms of their putative antioxidant effects remain largely uncharacterised. The vicinal thiols present in the reduced forms of these compounds suggest that they might possess metal chelating properties. We have shown previously that cell death caused by oxidants may be initiated by lysosomal rupture and that this latter event may involve intralysosomal iron which catalyzes Fenton-type chemistry and resultant peroxidative damage to lysosomal membranes. Here, using cultured J774 cells as a model, we show that both LA and LM stabilize lysosomes against oxidative stress, probably by chelating intralysosomal iron and, consequently, preventing intralysosomal Fenton reactions. In preventing oxidant-mediated apoptosis, LM is significantly more effective than LA, as would be expected from their differing capacities to enter cells and concentrate within the acidic lysosomal compartment. As previously reported, the powerful iron-chelator, desferrioxamine (Des) (which also locates within the lysosomal compartment), also provides protection against oxidant-mediated cell death. Interestingly, although Des enhances the partial protection afforded by LA, it confers no additional protection when added with LM. Therefore, the antioxidant actions of LA and LM may arise from intralysosomal iron chelation, with LM being more effective in this regard.

Place, publisher, year, edition, pages
2001. Vol. 6, no 5, 327-334 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-47165DOI: 10.1179/135100001101536472OAI: oai:DiVA.org:liu-47165DiVA: diva2:268061
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Prevention of oxidant-induced cell death by intralysosomal iron binding
Open this publication in new window or tab >>Prevention of oxidant-induced cell death by intralysosomal iron binding
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The lung is particularly prone to oxidative stress by its exposure to ambient oxygen and inhaled environmental oxidants. Abnormal assimilation and accumulation of iron are found in many lung disorders, which in redox-active form will exacerbate oxidative tissue damage. It may be that the most important cellular pool of redox -active iron exists within lysosomes. As a result, these organelles are very vulnerable to oxidative stress and may burst due to peroxidative membrane destabilization. Support for the importance of intralysosomal iron in cellular oxidant damage includes the observation that the iron chelator, desferrioxamine, which almost exclusively localizes within the lysosomal compartment, will protect cells against oxidati ve challenge. Iron chelators targeted to the lysosomes may therefore be a particularly efficient therapeutic strategy for cells under conditions of substantial oxidative stress.

The present study, employing cultures of human respiratory epithelial cells and murine macrophage-like cells, explores the protective effects by iron binding agents upon H202 and gamma radiation-induced lysosomal damage and cell death. Using these in vitro models, the present study shows: (1) that chelation of intralysosomal iron efficiently prevents lysosomal rupture and ensuing cell death induced by either H202 or gamma radiation; (2) that cell permeable lysosomotropic iron-chelators are much more efficient than those being internalized by endocytosis; (3) that intralysosomal iron is the most important cellular pool of redox-active iron for chelation therapy; (4) that ironcatalyzed peroxidative lysosomal destabilization is a decisive and early event in the apoptotic machinery.

Although apoferritin and desferrioxarnine suppress the reactivity of lysosomal iron, their efficacy is considerably restrained by their uptake by fluid-phase endocytosis. Apoferritin is digested intralysosomally which further decreases its iron sequestering potential, while desferrioxamine by its intralysosomal retention may disturbe normal cellular functions and cause iron-starvation. Amongst cell permeable iron-binding agents we tested a-lipoic acid, alipoamide, and a synthetic amine derivative of α-lipoarnide, α-lipoic acid-plus (5-[1,2] dithiolan-3-yl-pentanoic acid (2-dimethylamino-ethyl) amide). The large difference in the protective potential of these cell permeant iron-chelators derives from their being localized in different cellular compartments, which lends further support that lysososomes contain the most important pool of chelatable redox-active iron. Indeed, a-lipoic acid-plus by its lysosomotropism was by all means the most efficient iron chelator. On a molar basis α-lipoic acid-plus was 4,000 to 5,000 times more effective than desferrioxamine to prevent lysosomal rupture and cell death induced by H202 or gamma radiation.

We conclude that iron chelating therapy targeted to the lysosomes is an efficient strategy to protect oxidatively stressed cells in vitro. A corresponding efficacy of such treatment in vivo, and in iron dependent pulmonary disorders in particular, needs to be explored.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2003. 60 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 812
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27537 (URN)12194 (Local ID)91-7373-502-7 (ISBN)12194 (Archive number)12194 (OAI)
Public defence
2003-10-23, Victoriasalen, Universitetssjukhuset, Linköping, 13:15 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-05Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Persson, LennartBrunk, Ulf

Search in DiVA

By author/editor
Persson, LennartBrunk, Ulf
By organisation
Pulmonary MedicineFaculty of Health SciencesPathology
In the same journal
Redox report
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 100 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf