Recently there has been a renewal of interest in mitochondrial dysfunction as a mediator of diverse forms of cell injury as a result of new insights into the mechanism for the mitochondrial permeability transition and recognition of the role of mitochondrial cytochrome c release in apoptosis. ATP production in the proximal tubule, a major site of injury during ischemic and toxic forms of acute renal failure, is especially sensitive to mitochondrial dysfunction because, depending on the segment, glcolysis is absent or minimal in proximal tubule cells in vivo. In studies during the present funding period, we have identified a mitochondrial lesion characterized by inhibition of electron transport in complex I associated with matrix condensation and partial deenergization as a functionally important form of mitochondrial injury during hypoxia/reoxygenation of freshly isolated rabbit proximal tubules that play a pivtal role in overall cellular recovery. The lesion: a) precedes the mitochondrial permeability transition and cytochrome c release; b) depresses energetic function of otherwise viable tubules for sustained periods; and c) is highly amenable to prevention and reversal by specific citric acid cycle metabolites that promote anaerobic pathways of intramitochondrial ATP production and electron transport or, under aerobic conditions, bypass the complex I block. The mitochondrial lesion is expressed both in freshly isolated tubules subjected to hypoxia/reoxygeation, and based on ultrastructural changes and modification by citric acid cycle metabolites, during ischemia/reperfusion in vivo. Our general hypothesis is that this form of mitochondrial dysfunction plays a critical role in the outcome of ischemic insults to the kidney and that its amelioration will beneficially impact on cell and tissue recovery from these insults. To test this hypothesis and further investigate its implications for understanding and treating ischemic acute renal failure we propose studies to: 1) Characterize the energetic deficit as it evolves during extended durations of hypoxia/reoxygenation and the effects of protective substrates to ameliorate it under those conditions. 2) Better define the mechanisms for the mitochondrial inner membrane abnormalities during the insult and their relative contributions to the energetic deficit. 3) Assess expression of the lesion and test efficacy of protective metabolites during ischemia/reperfusion of the kidney in vivo.
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