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L-OPA1 regulates mitoflash biogenesis independently from membrane fusion

Santo-Domingo, Jaime
Published in EMBO reports. 2017, vol. 18, no. 3, p. 451-463
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 ApoptosisBiosensing TechniquesDynamins/genetics/metabolismEtoposide/pharmacologyGTP Phosphohydrolases/genetics/metabolismGene ExpressionHeLa CellsHumansHydrogen Peroxide/pharmacologyHydrogen-Ion ConcentrationMembrane FusionMembrane PotentialMitochondrialMitochondria/drug effects/genetics/metabolism/ultrastructureMitochondrial DynamicsMitochondrial Membranes/metabolismProteolysis
PMID: 28174208
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Article (Published version) (1.7 MB) - public document Free access
Research group Signaux intracellulaires (210)
Swiss National Science Foundation: 31003A_149566
(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 https://archive-ouverte.unige.ch/unige:100202

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Deposited on : 2017-12-12

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