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.
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