The role of iron in mitochondrial function

Levi, Sonia; Rovida, Ermanna

doi:10.1016/j.bbagen.2008.09.008

Cited by 168 publications

(127 citation statements)

References 125 publications

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“…This is probably due to the loss of ETC complex activity, causing leakage of free electrons during electron transport and producing superoxide radicals (43)(44)(45). Additionally, enrichment of the reduced form of iron in the mitochondria leads to production of superoxide radicals and highly toxic hydroxyl radicals through Fenton's reaction (46,47). These superoxide and hydroxyl radicals are detrimental to the cellular components as they inflict further damage to the pre-existing Fe-S clusters present in the ETC and other enzyme complexes.…”

Section: Discussionmentioning

confidence: 99%

Mapping Key Residues of ISD11 Critical for NFS1-ISD11 Subcomplex Stability

Saha

Srivastava

Kumar

et al. 2015

Journal of Biological Chemistry

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Background: NFS1-ISD11 complex is essential for the Fe-S cluster assembly process and the homozygous R68L ISD11 mutation causes the mitochondrial disorder, COXPD19. Results: Putative helix-3 and the C terminus of ISD11 are critical for NFS1-ISD11 subcomplex formation and Fe-S cluster biogenesis. Conclusion: ISD11 interaction is critical for NFS1 stability and its steady-state levels, in vivo. Significance: Identified important ISD11 residues will provides valuable information to understand COXPD19 progression.

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Section: Discussionmentioning

confidence: 99%

Mapping Key Residues of ISD11 Critical for NFS1-ISD11 Subcomplex Stability

Saha

Srivastava

Kumar

et al. 2015

Journal of Biological Chemistry

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“…Low-mass iron is physiologically available in lysosomes, mainly deriving from the breakdown of autophagocytosed ferruginous materials, 25,41 such as ferritin and mitochondria that carry the major share of intracellular iron. 42 Upon degradation of the protein backbone, bound iron is freed in the lysosomal lumen and kept in ferrous (Fe 2+ ) form by the low pH and the reducing environment of lysosomes. 17,43 Its redoxreactive configuration makes intralysosomal iron very prone to participate in Fenton-like reactions in the presence of H 2 O 2 .…”

Section: Discussionmentioning

confidence: 99%

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

et al. 2015

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, tandem fluorescent microtubule-associated protein 1 light chain 3 A/B (green/red fluorescent proteins chimera); TNFRSF1A/TNFR1, tumor necrosis factor receptor superfamily member 1A; TNFRSF1B/TNFR2, tumor necrosis factor receptor superfamily member 1B.Lysosomal membrane permeabilization (LMP) induced by oxidative stress has recently emerged as a prominent mechanism behind TNF cytotoxicity. This pathway relies on diffusion of hydrogen peroxide into lysosomes containing redox-active iron, accumulated by breakdown of iron-containing proteins and subcellular organelles. Upon oxidative lysosomal damage, LMP allows relocation to the cytoplasm of low mass iron and acidic hydrolases that contribute to DNA and mitochondrial damage, resulting in death by apoptosis or necrosis. Here we investigate the role of lysosomes and free iron in death of HTC cells, a rat hepatoma line, exposed to TNF following metallothionein (MT) upregulation. Iron-binding MT does not normally occur in HTC cells in significant amounts. Intracellular iron chelation attenuates TNF and cycloheximide (CHX)-induced LMP and cell death, demonstrating the critical role of this transition metal in mediating cytokine lethality. MT upregulation, combined with starvation-activated MT autophagy almost completely suppresses TNF and CHX toxicity, while impairment of both autophagy and MT upregulation by silencing of Atg7, and Mt1a and/or Mt2a, respectively, abrogates protection. Interestingly, MT upregulation by itself has little effect, while stimulated autophagy alone depresses cytokine toxicity to some degree. These results provide evidence that intralysosomal iron-catalyzed redox reactions play a key role in TNF and CHX-induced LMP and toxicity. The finding that chelation of intralysosomal iron achieved by autophagic delivery of MT, and to some degree probably of other ironbinding proteins as well, into the lysosomal compartment is highly protective provides a putative mechanism to explain autophagy-related suppression of death by TNF and CHX.

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“…proteolysis | Hsp70 | aging | Saccharomyces cerevisiae I ron, a critical element for virtually all living organisms, has a number of essential cellular roles. For example, heme, a critical iron-containing prosthetic group whose first and last biosynthetic steps occur in mitochondria, serves important roles in oxygen sensing and electron transfer (1). Most pertinent to the present work, iron-sulfur (Fe-S) clusters are a versatile prosthetic group found on proteins that play crucial roles in electron transport, catalytic reactions, environmental sensing, and regulation (1,2).…”

mentioning

confidence: 99%

“…For example, heme, a critical iron-containing prosthetic group whose first and last biosynthetic steps occur in mitochondria, serves important roles in oxygen sensing and electron transfer (1). Most pertinent to the present work, iron-sulfur (Fe-S) clusters are a versatile prosthetic group found on proteins that play crucial roles in electron transport, catalytic reactions, environmental sensing, and regulation (1,2). Given that iron enhances the production of intracellular reactive oxygen species that damage cellular macromolecules, it is not surprising that the level of cellular iron is tightly regulated.…”

mentioning

confidence: 99%

Cysteine desulfurase Nfs1 and Pim1 protease control levels of Isu, the Fe-S cluster biogenesis scaffold

Song

Marszałek

Craig

2012

Proc. Natl. Acad. Sci. U.S.A.

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Fe-S clusters are critical prosthetic groups for proteins involved in various critical biological processes. Before being transferred to recipient apo-proteins, Fe-S clusters are assembled on the highly conserved scaffold protein Isu, the abundance of which is regulated posttranslationally on disruption of the cluster biogenesis system. Here we report that Isu is degraded by the Lon-type AAA+ ATPase protease of the mitochondrial matrix, Pim1. Nfs1, the cysteine desulfurase responsible for providing sulfur for cluster formation, is required for the increased Isu stability occurring after disruption of cluster formation on or transfer from Isu. Physical interaction between the Isu and Nfs1 proteins, not the enzymatic activity of Nfs1, is the important factor in increased stability. Analysis of several conditions revealed that high Isu levels can be advantageous or disadvantageous, depending on the physiological condition. During the stationary phase, elevated Isu levels were advantageous, resulting in prolonged chronological lifespan. On the other hand, under iron-limiting conditions, high Isu levels were deleterious. Compared with cells expressing normal levels of Isu, such cells grew poorly and exhibited reduced activity of the heme-containing enzyme ferric reductase. Our results suggest that modulation of the degradation of Isu by the Pim1 protease is a regulatory mechanism serving to rapidly help balance the cell's need for critical ironrequiring processes under changing environmental conditions. proteolysis | Hsp70 | aging | Saccharomyces cerevisiae

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The role of iron in mitochondrial function

Cited by 168 publications

References 125 publications

Mapping Key Residues of ISD11 Critical for NFS1-ISD11 Subcomplex Stability

Mapping Key Residues of ISD11 Critical for NFS1-ISD11 Subcomplex Stability

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

Cysteine desulfurase Nfs1 and Pim1 protease control levels of Isu, the Fe-S cluster biogenesis scaffold

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