title: Bax/Bak-dependent release of DDP/TIMM8a promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death.
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.
authors.affiliation: Cellular Neurology Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Arnoult
authors.forename: Neggy
authors.initials: N
authors.lastname: Rismanchi
authors.forename: Alain
authors.initials: A
authors.lastname: Grodet
authors.forename: Roland G
authors.initials: RG
authors.lastname: Roberts
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Seeburg
authors.forename: Jérôme
authors.initials: J
authors.lastname: Estaquier
authors.forename: Morgan
authors.initials: M
authors.lastname: Sheng
authors.forename: Craig
authors.initials: C
authors.lastname: Blackstone
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003593:Cytoplasm / Q000378:metabolism; D017931:DNA Primers; D064550:Death-Associated Protein Kinases; D005455:Fluorescent Antibody Technique; D005982:Glutathione Transferase; D006367:HeLa Cells; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D020798:Two-Hybrid System Techniques; D015003:Yeasts; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; D017931:DNA Primers; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C118122:TIMM8A protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D005982:Glutathione Transferase; D064550:Death-Associated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases