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1 Division of Nephrology, Department of Internal Medicine, University of Michigan and Veteran's Administration Medical Center, Ann Arbor, MI, USA; Division of Nephrology and Hypertension, Department of Internal Medicine, University Hospital Essen, Ann Arbor, MI, USA
2 Division of Nephrology and Hypertension, Department of Internal Medicine, University Hospital Essen, Ann Arbor, MI, USA
3 Division of Nephrology, Department of Internal Medicine, University of Michigan and Veteran's Administration Medical Center, Ann Arbor, MI, USA
4 Department of Pathology and Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
5 Division of Child Development, Children's Hospital of Philadelphia, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: wnberg{at}umich.edu.
Inhibition of complex I has been considered to be an important contributor to mitochondrial dysfunction in tissues subjected to ischemia/reperfusion. We have investigated the role of complex I in a severe energetic deficit that develops in kidney proximal tubules subjected to hypoxia/reoxygenation and is strongly ameliorated by supplementation with specific citric acid cycle metabolites, including succinate and the combination of 
-ketoglutarate plus malate. NADH:ubiquinone reductase activity in the tubules was decreased by only 26% during 60 min. hypoxia and did not further change during 60 min. reoxygenation. During titration of complex I activity with rotenone, progressive reduction of NAD+ to NADH was detected at >20% complex I inhibition, but substantial decreases of ATP levels and mitochondrial membrane potential did not occur until >70% inhibition. NAD+ was reduced to NADH during hypoxia, but the NADH formed was fully reoxidized during reoxygenation, consistent with the conclusion that complex I function was not limiting for recovery. Extensive degradation of cytosolic and mitochondrial NAD(H) pools occurred during either hypoxia or severe electron transport inhibition by rotenone with patterns of metabolite accumulation consistent with catabolism by both NAD+ glycohydrolase and pyrophosphatase. This degradation was strongly blocked by -ketoglutarate plus malate. The data demonstrate surprisingly little sensitivity of these cells to inhibition of complex I and high levels of resistance to development of complex I dysfunction during hypoxia/reoxygenation, and indicate that events upstream of complex I are important for the energetic deficit. The work provides new insight into fundamental aspects of mitochondrial pathophysiology in proximal tubules during acute renal failure.
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