title: Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization.
abstract: Controversy surrounds the role and mechanism of mitochondrial cristae remodeling in apoptosis. Here we show that the proapoptotic BH3-only proteins Bid and Bim induced full cytochrome c release but only a subtle alteration of crista junctions, which involved the disassembly of Opa1 complexes. Both mitochondrial outer membrane permeabilization (MOMP) and crista junction opening (CJO) were caspase independent and required a functional BH3 domain and Bax/Bak. However, MOMP and CJO were experimentally separable. Pharmacological blockade of MOMP did not prevent Opa1 disassembly and CJO; moreover, expression of a disassembly-resistant mutant Opa1 (Q297V) blocked cytochrome c release and apoptosis but not Bax activation. Thus, apoptosis requires a subtle form of Opa1-dependent crista remodeling that is induced by BH3-only proteins and Bax/Bak but independent of MOMP.
authors.affiliation: La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Yamaguchi
authors.affiliation: La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Lydia
authors.initials: L
authors.lastname: Lartigue
authors.affiliation: Department of Neurosciences and National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Guy
authors.initials: G
authors.lastname: Perkins
authors.affiliation: Department of Neurosciences and National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ray T
authors.initials: RT
authors.lastname: Scott
authors.affiliation: Department of Neurosciences and National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Amruta
authors.initials: A
authors.lastname: Dixit
authors.affiliation: La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Kushnareva
authors.affiliation: Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kuwana
authors.affiliation: Department of Neurosciences and National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.affiliation: La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA. Electronic address: don@liai.org.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Newmeyer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000648:ultrastructure; D050505:Mutant Proteins / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D020836:Protein Structure, Quaternary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D007976:Leupeptins; D008565:Membrane Proteins; D050505:Mutant Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde