OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion.
Mitochondria amplify activation of caspases during apoptosis by releasing cytochrome c and other cofactors. This is accompanied by fragmentation of the organelle and remodeling of the cristae. Here we provide evidence that Optic Atrophy 1 (OPA1), a profusion dynamin-related protein of the inner mitochondrial membrane mutated in dominant optic atrophy, protects from apoptosis by preventing cytochrome c release independently from mitochondrial fusion. OPA1 does not interfere with activation of the mitochondrial "gatekeepers" BAX and BAK, but it controls the shape of mitochondrial cristae, keeping their junctions tight during apoptosis. Tightness of cristae junctions correlates with oligomerization of two forms of OPA1, a soluble, intermembrane space and an integral inner membrane one. The proapoptotic BCL-2 family member BID, which widens cristae junctions, also disrupts OPA1 oligomers. Thus, OPA1 has genetically and molecularly distinct functions in mitochondrial fusion and in cristae remodeling during apoptosis.
Frezza
Christian
C
Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy.
Cipolat
Sara
S
Martins de Brito
Olga
O
Micaroni
Massimo
M
Beznoussenko
Galina V
GV
Rudka
Tomasz
T
Bartoli
Davide
D
Polishuck
Roman S
RS
Danial
Nika N
NN
De Strooper
Bart
B
Scorrano
Luca
L
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D008561:Membrane Fusion / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism* / Q000648:ultrastructure; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019108:Tight Junctions / Q000378:metabolism / Q000648:ultrastructure; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse