Proteolytic Cleavage of Opa1 Stimulates Mitochondrial Inner Membrane Fusion and Couples Fusion to Oxidative Phosphorylation

• Mitochondrial inner membrane fusion is stimulated by oxidative phosphorylation
• Cleavage of Opa1 by Yme1L couples inner membrane fusion to metabolism
• Opa1 cleavage stimulates mitochondrial inner membrane fusion
• Diseases of mtDNA disrupt the linkage of oxidative phosphorylation to fusion

SummaryMitochondrial 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.

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