Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase

Nat Cell Biol. 2011 Sep 18;13(10):1224-33. doi: 10.1038/ncb2330.

Abstract

Anti-apoptotic Bcl2 family proteins such as Bcl-x(L) protect cells from death by sequestering apoptotic molecules, but also contribute to normal neuronal function. We find in hippocampal neurons that Bcl-x(L) enhances the efficiency of energy metabolism. Our evidence indicates that Bcl-x(L)interacts directly with the β-subunit of the F(1)F(O) ATP synthase, decreasing an ion leak within the F(1)F(O) ATPase complex and thereby increasing net transport of H(+) by F(1)F(O) during F(1)F(O) ATPase activity. By patch clamping submitochondrial vesicles enriched in F(1)F(O) ATP synthase complexes, we find that, in the presence of ATP, pharmacological or genetic inhibition of Bcl-x(L) activity increases the membrane leak conductance. In addition, recombinant Bcl-x(L) protein directly increases the level of ATPase activity of purified synthase complexes, and inhibition of endogenous Bcl-x(L) decreases the level of F(1)F(O) enzymatic activity. Our findings indicate that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-x(L)-expressing neurons.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Biphenyl Compounds / pharmacology
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology
  • Cells, Cultured
  • Energy Metabolism* / drug effects
  • Enzyme Inhibitors / pharmacology
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / enzymology*
  • Hydrolysis
  • Membrane Potential, Mitochondrial
  • Mitochondria / drug effects
  • Mitochondria / enzymology*
  • Mitochondrial Membranes / enzymology
  • Mitochondrial Proton-Translocating ATPases / antagonists & inhibitors
  • Mitochondrial Proton-Translocating ATPases / metabolism*
  • Neurons / drug effects
  • Neurons / enzymology*
  • Nitrophenols / pharmacology
  • Oligomycins / pharmacology
  • Oxygen Consumption
  • Patch-Clamp Techniques
  • Piperazines / pharmacology
  • Proton Ionophores / pharmacology
  • RNA Interference
  • Rats
  • Recombinant Fusion Proteins / metabolism
  • Sulfonamides / pharmacology
  • Synapses / drug effects
  • Synapses / enzymology*
  • Time Factors
  • Transfection
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / antagonists & inhibitors
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism*

Substances

  • ABT-737
  • Bak1 protein, rat
  • Bax protein, rat
  • Bcl2l1 protein, rat
  • Biphenyl Compounds
  • Enzyme Inhibitors
  • Nitrophenols
  • Oligomycins
  • Piperazines
  • Proton Ionophores
  • Recombinant Fusion Proteins
  • Sulfonamides
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
  • Adenosine Triphosphate
  • Mitochondrial Proton-Translocating ATPases