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Chelation of intralysosomal redox-active iron protects against ionizing radiation damage
Linköping University, Department of Neuroscience and Locomotion, Pathology. 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.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The mechanisms involved in cellular injury and death caused by ionizing radiation remain incompletely understood. Although DNA damage - especially to actively dividing cells - is certainly a critical component, other types of damage may also be important. Ionizing radiation generates reactive oxygen species (ROS) and 'loose' (i.e., redox-active) iron amplifies the damaging effects of ROS. The major pool of reactive intracellular iron may reside within the acidic vacuolar compartment (lysosomes and late endosomes). Lysosomes are responsible for the continuous digestion of ferruginous materials such as fenitin, mitochondria, and various metalloproteins. We have investigated the possible importance of intralysosomal iron and lysosomal rupture in radiation-induced cellular injury using macrophage-like J774 cells. We find: (i) Gamma radiation of cells greatly enhances the intracellular pool of reactive iron, which increase ≈ 5-fold 24 hours following a non-lethal single dose of radiation (40 Gy). (ii) Using a special staining procedure (the sulfide-silver method or auto-metallography), we find that most redox-active iron resides within the lysosomal compartment both before and after radiation. The dramatically increased intralysosomal iron following radiation probably derives from reparatin· autophagocytosis, whereby damaged iron-containing cellular constituents are digested intralysosomally. (iii) This increased lysosomal iron sensitizes cells to a second dose of radiation (20 Gy), which results in lysosomal rupture and ensuing apoptosis or necrosis. The enhanced sensitivity to radiation-induced lysosomal rupture is very likely linked to lysosomal iron: two chemically distinct iron chelators, HMW-DFO and LAP, which specifically localize within the lysosomal compartment, stabilize lysosomes and prevent cell death. These observations provide a biological rationale for fractionated radiation, in that a primary dose of radiation causes increased intralysosomal iron and synergizes the damage from a second dose of radiation. The resultant lysosomal rupture may not only lead directly to cell death, as we have proposed elsewhere, but iron released from lysosomes may relocate to the nucleus, intensifying radiation-mediated DNA damage. These findings should be useful in the design of more effective regimens of fractionated radiation and in designing new therapeutic modalities for the prevention of incidental radiationinduced death of normal tissues.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-84369OAI: oai:DiVA.org:liu-84369DiVA: diva2:558827
Available from: 2012-10-05 Created: 2012-10-05 Last updated: 2012-10-05Bibliographically 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

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Persson, LennartEaton, John WallaceBrunk, Ulf

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