Succinate ameliorates energy deficits and prevents dysfunction of complex I in injured renal proximal tubular cells

J Pharmacol Exp Ther. 2008 Mar;324(3):1155-62. doi: 10.1124/jpet.107.130872. Epub 2007 Nov 30.

Abstract

We previously reported that mitochondrial function, intracellular ATP levels, and complex I activity are decreased in renal proximal tubular cells (RPTC) after oxidant (tert-butyl hydroperoxide; TBHP)-induced injury. This study examined the hypothesis that succinate supplementation decreases mitochondrial dysfunction, ameliorates energy deficits, and increases viability in TBHP-injured RPTC. Basal and uncoupled respirations in injured RPTC decreased 33 and 35%, respectively, but remained unchanged in injured RPTC supplemented with 10 mM succinate (electron donor to respiratory complex II). State 3 respiration supported by electron donors to complex I decreased 40% in injured RPTC but improved significantly by succinate supplements. The activity of mitochondrial complex I in TBHP-injured RPTC decreased 48%, whereas complex II activity remained unchanged. Succinate supplementation prevented decreases in complex I activity. ATP levels decreased 43% in injured RPTC but were maintained in injured cells supplemented with succinate. Lipid peroxidation increased 19-fold in injured RPTC but only 9-fold in injured cells supplemented with succinate. Exposure of primary cultures of RPTC to TBHP produced 24% cell injury and lysis but no apoptosis. In contrast, no cell lysis was found in RPTC supplemented with succinate. We conclude that mitochondrial dysfunction and energy deficits in oxidant-injured RPTC are ameliorated by succinate, and we propose that succinate supplementation may prove therapeutically valuable. Succinate 1) uses an alternate pathway of mitochondrial energy metabolism, 2) improves activity of complex I and oxidation of substrates through complex I, and 3) decreases oxidative stress and cell lysis in oxidant-injured RPTC.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Respiration / drug effects
  • Cell Respiration / physiology
  • Cells, Cultured
  • Electron Transport Complex I / metabolism*
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology*
  • Female
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / injuries*
  • Kidney Tubules, Proximal / metabolism*
  • Oxygen Consumption / drug effects
  • Oxygen Consumption / physiology
  • Rabbits
  • Succinic Acid / pharmacology*

Substances

  • Succinic Acid
  • Electron Transport Complex I