Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization

Cell. 2010 Sep 17;142(6):889-901. doi: 10.1016/j.cell.2010.08.017.

Abstract

In response to many apoptotic stimuli, oligomerization of Bax is essential for mitochondrial outer membrane permeabilization and the ensuing release of cytochrome c. These events are accompanied by mitochondrial fission that appears to require Drp1, a large GTPase of the dynamin superfamily. Loss of Drp1 leads to decreased cytochrome c release by a mechanism that is poorly understood. Here we show that Drp1 stimulates tBid-induced Bax oligomerization and cytochrome c release by promoting tethering and hemifusion of membranes in vitro. This function of Drp1 is independent of its GTPase activity and relies on arginine 247 and the presence of cardiolipin in membranes. In cells, overexpression of Drp1 R247A/E delays Bax oligomerization and cell death. Our findings uncover a function of Drp1 and provide insight into the mechanism of Bax oligomerization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Cardiolipins / metabolism
  • Cell-Free System
  • GTP Phosphohydrolases / metabolism*
  • HeLa Cells
  • Humans
  • Liposomes / metabolism
  • Microtubule-Associated Proteins / metabolism*
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Rats
  • bcl-2-Associated X Protein / metabolism*

Substances

  • BH3 Interacting Domain Death Agonist Protein
  • Cardiolipins
  • Liposomes
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • bcl-2-Associated X Protein
  • GTP Phosphohydrolases
  • DNM1L protein, human