Frataxin, iron-sulfur clusters, heme, ROS, and aging

Research output: Contribution to journalArticle

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Abstract

A deficiency in mitochondrial frataxin causes an increased generation of mitochondrial reactive oxygen species (ROS), which may contribute to the cell degenerative features of Friedreich's ataxia. In this work the authors demonstrate mitochondrial iron-sulfur cluster (ISC) defects and mitochondrial heme defects, and suggest how both may contribute to increased mitochondrial ROS in lymphoblasts from human patients. Mutant cells are deficient in the ISC-requiring mitochondrial enzymes aconitase and succinate dehydrogenase, but not in the non-ISC mitochondrial enzyme citrate synthase; also, the mitochondrial iron-sulfur scaffold protein IscU2 co-immunoprecipitates with frataxia in vivo. Presumably as a consequence of the iron-sulfur cluster defect, cytochrome c heme is deficient in mutants, as well as heme-dependent Complex IV. Mitochondrial superoxide is elevated in mutants, which may be a consequence of cytochrome c deficiency. Hydrogen peroxide, glutathione peroxidase activity, and oxidized glutathione (GSSG) are each elevated in mutants, consistent with activation of the glutathione peroxidase pathway. Mutant status blunted the effects of Complex III and IV inhibitors, but not a Complex I inhibitor, on superoxide production. This suggests that heme defects late in the electron transport chain of mutants are responsible for increased mutant superoxide. The impact of ISC and heme defects on ROS production with age are discussed.

Original languageEnglish (US)
Pages (from-to)506-516
Number of pages11
JournalAntioxidants and Redox Signaling
Volume8
Issue number3-4
DOIs
StatePublished - Mar 2006

Fingerprint

Heme
Sulfur
Reactive Oxygen Species
Iron
Aging of materials
Superoxides
Defects
Glutathione Disulfide
Glutathione Peroxidase
Cytochromes c
Iron-Sulfur Proteins
Aconitate Hydratase
Friedreich Ataxia
Citrate (si)-Synthase
Succinate Dehydrogenase
Electron Transport Complex III
Mitochondrial Proteins
Enzymes
Electron Transport
Hydrogen Peroxide

ASJC Scopus subject areas

  • Biochemistry

Cite this

Frataxin, iron-sulfur clusters, heme, ROS, and aging. / Napoli, Eleonora; Taroni, Franco; Cortopassi, Gino A.

In: Antioxidants and Redox Signaling, Vol. 8, No. 3-4, 03.2006, p. 506-516.

Research output: Contribution to journalArticle

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