Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage.
The dynamin-related protein Opa1 is localized to the mitochondrial intermembrane space, where it facilitates fusion between mitochondria. Apoptosis causes Opa1 release into the cytosol and causes mitochondria to fragment. Loss of mitochondrial membrane potential also causes mitochondrial fragmentation but not Opa1 release into the cytosol. Both conditions induce the proteolytic cleavage of Opa1, suggesting that mitochondrial fragmentation is triggered by Opa1 inactivation. The opposite effect was observed with knockdown of the mitochondrial intermembrane space protease Yme1. Knockdown of Yme1 prevents the constitutive cleavage of a subset of Opa1 splice variants but does not affect carbonyl cyanide m-chlorophenyl hydrazone or apoptosis-induced cleavage. Knockdown of Yme1 also increases mitochondrial connectivity, but this effect is independent of Opa1 because it also occurs in Opa1 knockdown cells. We conclude that Yme1 constitutively regulates a subset of Opa1 isoforms and an unknown mitochondrial morphology protein, whereas the loss of membrane potential induces the further proteolysis of Opa1.
Griparic
Lorena
L
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Kanazawa
Takayuki
T
van der Bliek
Alexander M
AM
D000074183:ATPases Associated with Diverse Cellular Activities; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007476:Ionophores / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
D007476:Ionophores; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D045726:Metalloproteases; C485223:PARL protein, human; D008666:Metalloendopeptidases; C410807:YME1L1 protein, human; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities
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