The human disease Friedreich's ataxia (FA) causes progressive age-related neurodegeneration and cardiomyopathy associated with increased mitochondrial oxidative stress and damage. This human cellular model allows intensive experimental testing of cause and effect relationships between increased mitochondrial reactive oxygen species (ROS), and downstream molecular damage, pathophysiology and cell death.
Specific aims of this study are: (1) to characterize the type of increased ROS that occurs in FA, (2) to quantify the contribution of increased ROS to damage of mitochondrial lipids, mtDNA, and proteins, (3) to quantify the effects of this damage on the major possible mitochondrial physiological endpoints, and (4) to rescue phenotypes by inhibitors specific for each step in the hypothetical chain, and test its validity at the biochemical and cellular level and in knockout organisms constructed in Aim 5. These molecular targets of mitochondrial and oxidative damage in human cells, once identified and validated as pathophysiologically relevant will serve as targets for further analysis in the more complex situation of aging in humans and animals.
|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|
|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|
|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|
Showing the most recent 10 out of 25 publications