Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization.
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.
Yamaguchi
Ryuji
R
La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
Lartigue
Lydia
L
La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
Perkins
Guy
G
Department of Neurosciences and National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093, USA.
Scott
Ray T
RT
Department of Neurosciences and National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093, USA.
Dixit
Amruta
A
Department of Neurosciences and National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093, USA.
Kushnareva
Yulia
Y
La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
Kuwana
Tomomi
T
Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Ellisman
Mark H
MH
Department of Neurosciences and National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093, USA.
Newmeyer
Donald D
DD
La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA. Electronic address: don@liai.org.
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*
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