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Scientific article
Open access
English

L-OPA1 regulates mitoflash biogenesis independently from membrane fusion

Published inEMBO Reports, vol. 18, no. 3, p. 451-463
Publication date2017
Abstract

Mitochondrial flashes mediated by optic atrophy 1 (OPA1) fusion protein are bioenergetic responses to stochastic drops in mitochondrial membrane potential (Δψm) whose origin is unclear. Using structurally distinct genetically encoded pH-sensitive probes, we confirm that flashes are matrix alkalinization transients, thereby establishing the pH nature of these events, which we renamed "mitopHlashes". Probes located in cristae or intermembrane space as verified by electron microscopy do not report pH changes during Δψm drops or respiratory chain inhibition. Opa1 ablation does not alter Δψm fluctuations but drastically decreases the efficiency of mitopHlash/Δψm coupling, which is restored by re-expressing fusion-deficient OPA1K301A and preserved in cells lacking the outer-membrane fusion proteins MFN1/2 or the OPA1 proteases OMA1 and YME1L, indicating that mitochondrial membrane fusion and OPA1 proteolytic processing are dispensable. pH/Δψm uncoupling occurs early during staurosporine-induced apoptosis and is mitigated by OPA1 overexpression, suggesting that OPA1 maintains mitopHlash competence during stress conditions. We propose that OPA1 stabilizes respiratory chain supercomplexes in a conformation that enables respiring mitochondria to compensate a drop in Δψm by an explosive matrix pH flash.

Keywords
  • Apoptosis
  • Biosensing Techniques
  • Dynamins/genetics/metabolism
  • Etoposide/pharmacology
  • GTP Phosphohydrolases/genetics/metabolism
  • Gene Expression
  • HeLa Cells
  • Humans
  • Hydrogen Peroxide/pharmacology
  • Hydrogen-Ion Concentration
  • Membrane Fusion
  • Membrane Potential
  • Mitochondrial
  • Mitochondria/drug effects/genetics/metabolism/ultrastructure
  • Mitochondrial Dynamics
  • Mitochondrial Membranes/metabolism
  • Proteolysis
Citation (ISO format)
ROSSELIN, Manon et al. L-OPA1 regulates mitoflash biogenesis independently from membrane fusion. In: EMBO Reports, 2017, vol. 18, n° 3, p. 451–463. doi: 10.15252/embr.201642931
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Article (Published version)
Identifiers
ISSN of the journal1469-221X
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