Mitochondrial complex II prevents hypoxic but not calcium- and proapoptotic Bcl-2 protein-induced mitochondrial membrane potential loss

J Biol Chem. 2010 Aug 20;285(34):26494-505. doi: 10.1074/jbc.M110.143164. Epub 2010 Jun 21.

Abstract

Mitochondrial membrane potential loss has severe bioenergetic consequences and contributes to many human diseases including myocardial infarction, stroke, cancer, and neurodegeneration. However, despite its prominence and importance in cellular energy production, the basic mechanism whereby the mitochondrial membrane potential is established remains unclear. Our studies elucidate that complex II-driven electron flow is the primary means by which the mitochondrial membrane is polarized under hypoxic conditions and that lack of the complex II substrate succinate resulted in reversible membrane potential loss that could be restored rapidly by succinate supplementation. Inhibition of mitochondrial complex I and F(0)F(1)-ATP synthase induced mitochondrial depolarization that was independent of the mitochondrial permeability transition pore, Bcl-2 (B-cell lymphoma 2) family proteins, or high amplitude swelling and could not be reversed by succinate. Importantly, succinate metabolism under hypoxic conditions restores membrane potential and ATP levels. Furthermore, a reliance on complex II-mediated electron flow allows cells from mitochondrial disease patients devoid of a functional complex I to maintain a mitochondrial membrane potential that conveys both a mitochondrial structure and the ability to sequester agonist-induced calcium similar to that of normal cells. This finding is important as it sets the stage for complex II functional preservation as an attractive therapy to maintain mitochondrial function during hypoxia.

Publication types

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

MeSH terms

  • Adenosine Triphosphate
  • Animals
  • Calcium / physiology*
  • Electron Transport Complex II / physiology*
  • Humans
  • Hypoxia*
  • Membrane Potential, Mitochondrial*
  • Mice
  • Mitochondrial Membrane Transport Proteins
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • Proton-Translocating ATPases / physiology
  • Rats
  • Succinic Acid / pharmacology

Substances

  • Mitochondrial Membrane Transport Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • mitochondrial permeability transition pore
  • Adenosine Triphosphate
  • Succinic Acid
  • Electron Transport Complex II
  • Proton-Translocating ATPases
  • Calcium