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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG016719-03
Application #
6372332
Study Section
Geriatrics and Rehabilitation Medicine (GRM)
Program Officer
Finkelstein, David B
Project Start
1999-04-15
Project End
2004-03-31
Budget Start
2001-05-01
Budget End
2002-03-31
Support Year
3
Fiscal Year
2001
Total Cost
$217,239
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
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
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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

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