Acidic pH amplifies iron-mediated lipid peroxidation in cells

Schäfer, Freya; Buettner, Garry R.

doi:10.1016/s0891-5849(00)00319-1

Cited by 112 publications

(67 citation statements)

References 21 publications

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“…The mitochondrial dysfunction in Hfe -/-mice, evidenced by decreased oxygen consumption, is consistent with oxidative damage and lipid peroxidation. Studies on cardiac reperfusion injury, for example, have demonstrated that treatment of cardiac mitochondria with 4-hydroxy-2-nonenal (HNE) results in decreased NADH-linked (complex-I) respiration, and other studies have implicated products of lipid peroxidation in altering cellular membrane permeability (38,39). Our data show that the iron accumulation in Hfe -/-mice occurs in the cytoplasm, but not mitochondria, suggesting that mitochondrial iron accumulation resulting in generation of reactive oxygen species by Fenton chemistry is not the major source of oxidative stress within the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Iron-Mediated Inhibition of Mitochondrial Manganese Uptake Mediates Mitochondrial Dysfunction in a Mouse Model of Hemochromatosis

Jouihan

Cobine

Cooksey

et al. 2008

Mol Med

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Previous phenotyping of glucose homeostasis and insulin secretion in a mouse model of hereditary hemochromatosis (Hfe -/-) and iron overload suggested mitochondrial dysfunction. Mitochondria from Hfe -/-mouse liver exhibited decreased respiratory capacity and increased lipid peroxidation. Although the cytosol contained excess iron, Hfe -/-mitochondria contained normal iron but decreased copper, manganese, and zinc, associated with reduced activities of copper-dependent cytochrome c oxidase and manganese-dependent superoxide dismutase (MnSOD). The attenuation in MnSOD activity was due to substantial levels of unmetallated apoprotein. The oxidative damage in Hfe -/-mitochondria is due to diminished MnSOD activity, as manganese supplementation of Hfe -/-mice led to enhancement of MnSOD activity and suppressed lipid peroxidation. Manganese supplementation also resulted in improved insulin secretion and glucose tolerance associated with increased MnSOD activity and decreased lipid peroxidation in islets. These data suggest a novel mechanism of iron-induced cellular dysfunction, namely altered mitochondrial uptake of other metal ions.

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Section: Discussionmentioning

confidence: 99%

Iron-Mediated Inhibition of Mitochondrial Manganese Uptake Mediates Mitochondrial Dysfunction in a Mouse Model of Hemochromatosis

Jouihan

Cobine

Cooksey

et al. 2008

Mol Med

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“…An additional way of loading lysosomes with iron is of importance when scavenger cells, such as macrophages, endocytose erythrocytes and thereby enrich their lysosomal compartment with redox-active iron. Because the lysosomal compartment is acidic and rich in reducing equivalents, such as cysteine and glutathione, any low mass iron would likely be Fe(II) (Schafer andBuettner, 2000, Terman et al, 2010). That in turn would promote the generation of hydroxyl radicals from hydrogen peroxide diffusing into this compartment.…”

Section: The Role Of Lysosomes In Intracellular Iron Metabolismmentioning

confidence: 99%

The role of lysosomes in iron metabolism and recycling

Kurz

Eaton

Brunk

2011

The International Journal of Biochemistry & Cell Biology

172

134

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Iron is the most abundant transition metal in the earths crust. It cycles easily between ferric (oxidized; Fe(III)) and ferrous (reduced; Fe(II)) and readily forms complexes with oxygen, making this metal a central player in respiration and related redox processes. However, loose iron, not within heme or iron-sulfur cluster proteins, can be destructively redox-active, causing damage to almost all cellular components, killing both cells and organisms. This may explain why iron is so carefully handled by aerobic organisms. Iron uptake from the environment is carefully limited and carried out by specialized iron transport mechanisms. One reason that iron uptake is tightly controlled is that most organisms and cells cannot efficiently excrete excess iron. When even small amounts of intracellular free iron occur, most of it is safely stored in a non-redox-active form in ferritins. Within nucleated cells, iron is constantly being recycled from aged iron-rich organelles such as mitochondria and used for construction of new organelles. Much of this recycling occurs within the lysosome, an acidic digestive organelle. Because of this, most lysosomes contain relatively large amounts of redox-active iron and are therefore unusually susceptible to oxidant-mediated destabilization or rupture. In many cell types, iron transit through the lysosomal compartment can be remarkably brisk. However, conditions adversely affecting lysosomal iron handling (or oxidant stress) can contribute to a variety of acute and chronic diseases. These considerations make normal and abnormal lysosomal handling of iron central to the understanding and, perhaps, therapy of a wide range of diseases

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“…Such low-mass iron is partially in the ferrous (FeII) state, due to an abundance in lysosomes of the reducing amino acid cysteine, a product of protein degradation. In the reducing acidic milieu of lysosomes, iron-catalysed peroxidation is particularly effective [79], and lipofuscin forms by complexing of aldehydes (developed secondary to fragmentation of lipid peroxides) with free amino groups of protein fragments [29,75]. Major factors enhancing lipofuscin formation are: a high level of autophagic activity; the pronounced formation of hydrogen peroxide (oxidative stress) or insignificant cytosolic degradation of the hydrogen peroxide that has been formed; and high concentrations within the lysosomes of low-mass redox-active iron [29,75].…”

Section: Mechanisms Of Lipofuscin Accumulationmentioning

confidence: 99%

Autophagy, organelles and ageing

Terman

Gustafsson

Brunk

2007

The Journal of Pathology

263

210

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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.

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Acidic pH amplifies iron-mediated lipid peroxidation in cells

Cited by 112 publications

References 21 publications

Iron-Mediated Inhibition of Mitochondrial Manganese Uptake Mediates Mitochondrial Dysfunction in a Mouse Model of Hemochromatosis

Iron-Mediated Inhibition of Mitochondrial Manganese Uptake Mediates Mitochondrial Dysfunction in a Mouse Model of Hemochromatosis

The role of lysosomes in iron metabolism and recycling

Autophagy, organelles and ageing

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