Bax/Bak-dependent release of DDP/TIMM8a promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death

Curr Biol. 2005 Dec 6;15(23):2112-8. doi: 10.1016/j.cub.2005.10.041.

Abstract

Mitochondrial morphology within cells is controlled by precisely regulated rates of fusion and fission . During programmed cell death (PCD), mitochondria undergo extensive fragmentation and ultimately caspase-independent elimination through a process known as mitoptosis . Though this increased fragmentation is due to increased fission through the recruitment of the dynamin-like GTPase Drp1 to mitochondria , as well as to a block in mitochondrial fusion , cellular mechanisms underlying these processes remain unclear. Here, we describe a mechanism for the increased mitochondrial Drp1 levels and subsequent stimulation of mitochondrial fission seen during PCD. We observed Bax/Bak-mediated release of DDP/TIMM8a, a mitochondrial intermembrane space (IMS) protein , into the cytoplasm, where it binds to and promotes the mitochondrial redistribution of Drp1, a mediator of mitochondrial fission. Using both loss- and gain-of-function assays, we also demonstrate that the Drp1- and DDP/TIMM8a-dependent mitochondrial fragmentation observed during PCD is an important step in mitoptosis, which in turn is involved in caspase-independent cell death. Thus, following Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), IMS proteins released comprise not only apoptogenic factors such as cytochrome c involved in caspase activation but also DDP/TIMM8a, which activates Drp1-mediated fission to promote mitochondrial fragmentation and subsequently elimination during PCD.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cytoplasm / metabolism
  • DNA Primers
  • Death-Associated Protein Kinases
  • Fluorescent Antibody Technique
  • Glutathione Transferase
  • HeLa Cells
  • Humans
  • Membrane Transport Proteins / metabolism*
  • Microscopy, Electron, Transmission
  • Mitochondria / metabolism
  • Mitochondria / physiology*
  • Molecular Sequence Data
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Two-Hybrid System Techniques
  • Yeasts
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • BAK1 protein, human
  • DNA Primers
  • Membrane Transport Proteins
  • TIMM8A protein, human
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • Glutathione Transferase
  • Death-Associated Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases