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.
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