Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation.
Mitochondrial fusion is essential for maintenance of mitochondrial function. The mitofusin GTPases control mitochondrial outer membrane fusion, whereas the dynamin-related GTPase Opa1 mediates inner membrane fusion. We show that mitochondrial inner membrane fusion is tuned by the level of oxidative phosphorylation (OXPHOS), whereas outer membrane fusion is insensitive. Consequently, cells from patients with pathogenic mtDNA mutations show a selective defect in mitochondrial inner membrane fusion. In elucidating the molecular mechanism of OXPHOS-stimulated fusion, we uncover that real-time proteolytic processing of Opa1 stimulates mitochondrial inner membrane fusion. OXPHOS-stimulated mitochondrial fusion operates through Yme1L, which cleaves Opa1 more efficiently under high OXPHOS conditions. Engineered cleavage of Opa1 is sufficient to mediate inner membrane fusion, regardless of respiratory state. Proteolytic cleavage therefore stimulates the membrane fusion activity of Opa1, and this feature is exploited to dynamically couple mitochondrial fusion to cellular metabolism.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Prashant
P
Mishra
IRCCS Istituto delle Scienze Neurologiche di Bologna, Department of Biomedical and NeuroMotor Sciences, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy.
Valerio
V
Carelli
Departments of Neurology and Neuroscience, Weill Medical College of Cornell University, 1300 York Avenue, A501, New York, NY 10065, USA.
Giovanni
G
Manfredi
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: dchan@caltech.edu.
David C
DC
Chan
D000818:Animals; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D008561:Membrane Fusion / Q000502:physiology*; D051379:Mice; D017237:Mitochondrial Encephalomyopathies / Q000503:physiopathology; D051336:Mitochondrial Membranes / Q000378:metabolism*; D053142:Mitochondrial Size / Q000502:physiology; D010085:Oxidative Phosphorylation; D059748:Proteolysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
D034741:RNA, Small Interfering; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse