title: Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization.
abstract: Mitochondrial outer-membrane permeabilization by pro-apoptotic Bcl-2 family members plays a crucial role in apoptosis induction. However, whether this directly causes the release of the different mitochondrial apoptogenic factors simultaneously is currently unknown. Here we report that in cells or with isolated mitochondria, pro-apoptotic Bcl-2 proteins cause the release of cytochrome c, Smac/Diablo and HtrA2/Omi but not endonuclease G (EndoG) and apoptosis-inducing factor (AIF). In cells treated with Bax/Bak-dependent pro-apoptotic drugs, neither the caspase inhibitor zVAD-fmk nor loss of Apaf-1 affected the efflux of cytochrome c, Smac/Diablo and HtrA2/Omi, but both prevented the release of EndoG and AIF. Our findings identify the mitochondrial response to pro-apoptotic stimuli as a selective process leading to a hierarchical ordering of the effectors involved in cell death induction. Moreover, as in Caenorhabditis elegans, EndoG and AIF act downstream of caspase activation. Thus EndoG and AIF seem to define a 'caspase-dependent' mitochondria-initiated apoptotic DNA degradation pathway that is conserved between mammals and nematodes.
authors.affiliation: Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Arnoult
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gaume
authors.forename: Mariusz
authors.initials: M
authors.lastname: Karbowski
authors.forename: Juanita C
authors.initials: JC
authors.lastname: Sharpe
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
mesh_terms: D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D017173:Caenorhabditis elegans / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D004789:Enzyme Activation; D005420:Flavoproteins / Q000378:metabolism*; D006367:HeLa Cells; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D010539:Permeability; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; C494815:Bid protein, mouse; D002352:Carrier Proteins; D003574:Cytochrome c Group; C412403:DIABLO protein, human; C499605:Diablo protein, mouse; D005420:Flavoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C494830:AIFM1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; D020169:Caspases; D019311:Staurosporine