Reduction in frataxin causes progressive accumulation of mitochondrial damage

Karthikeyan, G.; Santos, Janine H.; Gra̧ziewicz, Maria A.; Copeland, William C.; Isaya, Grazia; Houten, Bennett Van; Resnick, Michael A.

doi:10.1093/hmg/ddg349

Cited by 95 publications

(72 citation statements)

References 66 publications

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“…In yeast, it was demonstrated that frataxin is involved in mitochondrial iron efflux (252) or iron storage (96,234). Turning off the yeast frataxin promoter in an inducible system caused accumulation of iron in mitochondria and resulted in mitochondrial and nuclear oxidative DNA damage (153). The frataxin-deficient yeast also showed more production of hydrogen peroxide, higher sensitivity to DNA-damaging agents, and increased chromosomal instability (152), suggesting that detoxification of mitochondrial iron is a primary function of frataxin (97).…”

Section: B Frataxin and Mitochondrial Iron Trafficmentioning

confidence: 99%

Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications

Mackenzie

Iwasaki

Tsuji

2008

Antioxidants & Redox Signaling

440

372

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Section: B Frataxin and Mitochondrial Iron Trafficmentioning

confidence: 99%

Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications

Mackenzie

Iwasaki

Tsuji

2008

Antioxidants & Redox Signaling

440

372

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“…Controlling the ability of iron to perform redox chemistry appears to be an additional function of frataxin, suggesting this protein may directly participate in controlling cellular oxidative stress by reducing ROS production. In vivo reports indicate frataxin deficiency leads to oxidative damage in humans (Emond et al, 2000;Schultz et al, 2000), mice (Ristow et al, 2003;Thierbach et al, 2005), yeast (Karthikeyan et al, 2003), and Caenorhabditis elegans (Vazquez-Manrique et al, 2006). Mitochondrial iron overload, resulting from a frataxin deficiency, leads to oxidative damage in mitochondrial and nuclear DNA as well as to Fe-S clusters in mitochondrial aconitase and other respiratory enzymes (Babcock et al, 1997;Foury, 1999;Karthikeyan et al, 2002).…”

Section: Frataxin Controls Iron's Redox Chemistrymentioning

confidence: 99%

The Structure and Function of Frataxin

Bencze

Kondapalli

Cook

et al. 2006

Critical Reviews in Biochemistry and Molecular Biology

144

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Frataxin, a highly conserved protein found in prokaryotes and eukaryotes, is required for efficient regulation of cellular iron homeostasis. Humans with a frataxin deficiency have the cardio-and neurodegenerative disorder Friedreich's ataxia, commonly resulting from a GAA trinucleotide repeat expansion in the frataxin gene. While frataxin's specific function remains a point of controversy, the general consensus is that the protein assists in controlling cellular iron homeostasis by directly binding iron. This review focuses on the structural and biochemical aspects of iron binding by the frataxin orthologs and outlines molecular attributes that may help explain the protein's role in different cellular pathways.

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“…Previous studies reported the defective respiration, unstable mitochondrial DNA, and hypersensitivity to oxidative stress that follow inactivation of the yeast frataxin homologue (Yfh1) (6,20). The impairment of mitochondrial iron metabolism, particularly FeS cluster and heme synthesis, was suggested to be the primary cause for this complex phenotype (48).…”

Section: Complementation Of Yeast Frataxin Mutantsmentioning

confidence: 99%

Frataxin, a Conserved Mitochondrial Protein, in the Hydrogenosome of Trichomonas vaginalis

et al. 2007

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Recent data suggest that frataxin plays a key role in eukaryote cellular iron metabolism, particularly in mitochondrial heme and iron-sulfur (FeS) cluster biosynthesis. We have now identified a frataxin homologue (T. vaginalis frataxin) from the human parasite Trichomonas vaginalis. Instead of mitochondria, this unicellular eukaryote possesses hydrogenosomes, peculiar organelles that produce hydrogen but nevertheless share common ancestry with mitochondria. T. vaginalis frataxin contains conserved residues implicated in iron binding, and in silico, it is predicted to form a typical ␣-␤ sandwich motif. The short N-terminal extension of T. vaginalis frataxin resembles presequences that target proteins to hydrogenosomes, a prediction confirmed by the results of overexpression of T. vaginalis frataxin in T. vaginalis. When expressed in the mitochondria of a frataxindeficient Saccharomyces cerevisiae strain, T. vaginalis frataxin partially restored defects in heme and FeS cluster biosynthesis. Although components of heme synthesis or heme-containing proteins have not been found in T. vaginalis to date, T. vaginalis frataxin was also shown to interact with S. cerevisiae ferrochelatase by using a Biacore assay. The discovery of conserved iron-metabolizing pathways in mitochondria and hydrogenosomes provides additional evidence not only of their common evolutionary history, but also of the fundamental importance of this pathway for eukaryotes.In eukaryotes, mitochondrial proteins play vital roles in cellular iron metabolism by inserting iron into two types of prosthetic groups: FeS clusters and heme. While the steps mediating porphyrin synthesis are partitioned between mitochondria and the cytosol, the final insertion of ferrous iron into the porphyrin ring occurs in the mitochondria by the activity of ferrochelatase (7). FeS cluster biosynthesis is catalyzed by a multiprotein machinery (25, 37) with a predominantly mitochondrial localization, although in higher eukaryotes, subpopulations of some components with extramitochondrial localizations were identified (31). The process is initiated by sulfur release from free cysteine by the activity of the cysteine desulfurase IscS (47). A protein-bound persulfide is combined with a still-undefined iron intermediate to form an FeS cluster on the scaffold protein IscU. Both the heme and FeS cluster synthesis pathways rely on an iron donor within the mitochondria to distribute iron, maintain its bioavailability, and reduce its deleterious effects via Fenton chemistry. The nature of such an iron donor remains unclear; however, the small mitochondrial protein frataxin is currently the leading candidate for this function.In humans, loss of frataxin function leads to the neurodegenerative disorder Friedreich's ataxia, which is manifested on the cellular level by mitochondrial iron accumulation, sensitivity to oxidants, depletion of mitochondrial DNA, impaired respiration, and decreased activities of FeS proteins (6,13,23,45). Because of the difficulties in distinguishing between pri...

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Reduction in frataxin causes progressive accumulation of mitochondrial damage

Cited by 95 publications

References 66 publications

Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications

Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications

The Structure and Function of Frataxin

Frataxin, a Conserved Mitochondrial Protein, in the Hydrogenosome of Trichomonas vaginalis

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