Our broad objective is to understand the disease mechanism of Friedreich's ataxia (FRDA), which appears to involve mitochondrial oxidative stress and cell death, as a model for mitochondrial pathophysiology in aging. Our studies in human cells have demonstrated a sensitivity of FRDA cells to oxidative insults, and mitochondrial bioenergetic defects, increases in mitochondrial free iron, and increased intrinsic mitochondrial oxidative stress, all of which are rescued by transfection of the frataxin gene. Our microarray data have supported two major mechanistic hypotheses for the disease--i.e. that there is an alteration in (iron) sulfur homeostasis in these cells, and an activation of the apoptotic program. Our current plan is to clarify the precise biochemical function of frataxin in human cells, using biochemical, molecular and cellular tests of (1) an iron-sulfur defect hypothesis, and (2) a deficiency in SAA pathway hypothesis, and (3) to demonstrate the order of pathophysiological events downstream of this initial defect. We further plan (4) to identify new ways to distinguish the mutant and control cells at the cellular level, and (5) to screen for, design and improve small-molecule inhibitors of the pathophysiological steps identified, to identify potential routes for anti-FRDA therapy.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-OBM-2 (05))
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Finkelstein, David B
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University of California Davis
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Shan, Yuxi; Cortopassi, Gino (2016) Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly. Mitochondrion 26:94-103
Hayashi, Genki; Cortopassi, Gino (2015) Oxidative stress in inherited mitochondrial diseases. Free Radic Biol Med 88:10-7
Shan, Yuxi; Cortopassi, Gino (2012) HSC20 interacts with frataxin and is involved in iron-sulfur cluster biogenesis and iron homeostasis. Hum Mol Genet 21:1457-69
Tomilov, Alexey A; Ramsey, Jon J; Hagopian, Kevork et al. (2011) The Shc locus regulates insulin signaling and adiposity in mammals. Aging Cell 10:55-65
Schoenfeld, Robert; Wong, Alice; Silva, Jillian et al. (2010) Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation. Mitochondrion 10:143-50
Tomilov, Alexey A; Bicocca, Vincent; Schoenfeld, Robert A et al. (2010) Decreased superoxide production in macrophages of long-lived p66Shc knock-out mice. J Biol Chem 285:1153-65
Duveau, Damien Y; Arce, Pablo M; Schoenfeld, Robert A et al. (2010) Synthesis and characterization of mitoQ and idebenone analogues as mediators of oxygen consumption in mitochondria. Bioorg Med Chem 18:6429-41
Silva, Jillian M; Wong, Alice; Carelli, Valerio et al. (2009) Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia. Neurobiol Dis 34:357-65
Rolo, Anabela P; Palmeira, Carlos M; Cortopassi, Gino A (2009) Biosensor plates detect mitochondrial physiological regulators and mutations in vivo. Anal Biochem 385:176-8
Lu, Chunye; Schoenfeld, Robert; Shan, Yuxi et al. (2009) Frataxin deficiency induces Schwann cell inflammation and death. Biochim Biophys Acta 1792:1052-61

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