Preservation of complex I function during hypoxia-reoxygenation-induced mitochondrial injury in proximal tubules

Thorsten Feldkamp, Andreas Kribben, Nancy F. Roeser, Ruth A. Senter, Sarah Kemner, Manjeri A Venkatachalam, Itzhak Nissim, Joel M. Weinberg

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

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 α-ketoglutarate plus malate. NADH: ubiquinone reductase activity in the tubules was decreased by only 26% during 60-min hypoxia and did not change further 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 in 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 α-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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume286
Issue number4 55-4
StatePublished - Apr 2004

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NAD
Wounds and Injuries
Rotenone
NAD+ Nucleosidase
Electron Transport Complex I
Proximal Kidney Tubule
Citric Acid Cycle
Mitochondrial Membrane Potential
Succinic Acid
Electron Transport
Acute Kidney Injury
Reperfusion
Hypoxia
Ischemia
Adenosine Triphosphate
malic acid

Keywords

  • Acute renal failure
  • ATP
  • Citric acid cycle
  • NADH

ASJC Scopus subject areas

  • Physiology

Cite this

Preservation of complex I function during hypoxia-reoxygenation-induced mitochondrial injury in proximal tubules. / Feldkamp, Thorsten; Kribben, Andreas; Roeser, Nancy F.; Senter, Ruth A.; Kemner, Sarah; Venkatachalam, Manjeri A; Nissim, Itzhak; Weinberg, Joel M.

In: American Journal of Physiology - Renal Physiology, Vol. 286, No. 4 55-4, 04.2004.

Research output: Contribution to journalArticle

Feldkamp, Thorsten ; Kribben, Andreas ; Roeser, Nancy F. ; Senter, Ruth A. ; Kemner, Sarah ; Venkatachalam, Manjeri A ; Nissim, Itzhak ; Weinberg, Joel M. / Preservation of complex I function during hypoxia-reoxygenation-induced mitochondrial injury in proximal tubules. In: American Journal of Physiology - Renal Physiology. 2004 ; Vol. 286, No. 4 55-4.
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