Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells.
The mammalian mitochondrial inner membrane fusion protein OPA1 is controlled by complex patterns of alternative splicing and proteolysis. A subset of OPA1 isoforms is constitutively cleaved by YME1L. Other isoforms are not cleaved by YME1L, but they are cleaved when mitochondria lose membrane potential or adenosine triphosphate. In this study, we show that this inducible cleavage is mediated by a zinc metalloprotease called OMA1. We find that OMA1 small interfering RNA inhibits inducible cleavage, helps retain fusion competence, and slows the onset of apoptosis, showing that OMA1 controls OPA1 cleavage and function. We also find that OMA1 is normally cleaved from 60 to 40 kD by another as of yet unidentified protease. Loss of membrane potential causes 60-kD protein to accumulate, suggesting that OMA1 is attenuated by proteolytic degradation. We conclude that a proteolytic cascade controls OPA1. Inducible cleavage provides a mechanism for quality control because proteolytic inactivation of OPA1 promotes selective removal of defective mitochondrial fragments by preventing their fusion with the mitochondrial network.
Head
Brian
B
Department of Biological Chemistry, University of California, Los Angeles, 90095, USA.
Griparic
Lorena
L
Amiri
Mandana
M
Gandre-Babbe
Shilpa
S
van der Bliek
Alexander M
AM
D017209:Apoptosis; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008564:Membrane Potentials; D008666:Metalloendopeptidases / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism; D034622:RNA Interference
D024101:Mitochondrial Proteins; D020033:Protein Isoforms; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D010447:Peptide Hydrolases; D008666:Metalloendopeptidases; C477817:molecule metalloprotease-related protein-1, human; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human