Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation

Prashant Mishra, Valerio Carelli, Giovanni Manfredi, David C. Chan

Research output: Contribution to journalArticle

143 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)630-641
Number of pages12
JournalCell Metabolism
Volume19
Issue number4
DOIs
StatePublished - Apr 1 2014

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Membrane Fusion
Oxidative Phosphorylation
Mitochondrial Dynamics
GTP Phosphohydrolases
Dynamins
Mitochondrial DNA
Maintenance
Mutation

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology
  • Medicine(all)

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Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. / Mishra, Prashant; Carelli, Valerio; Manfredi, Giovanni; Chan, David C.

In: Cell Metabolism, Vol. 19, No. 4, 01.04.2014, p. 630-641.

Research output: Contribution to journalArticle

Mishra, Prashant ; Carelli, Valerio ; Manfredi, Giovanni ; Chan, David C. / Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. In: Cell Metabolism. 2014 ; Vol. 19, No. 4. pp. 630-641.
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