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L‐ OPA 1 regulates mitoflash biogenesis independently from membrane fusion

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Title: L‐ OPA 1 regulates mitoflash biogenesis independently from membrane fusion
Authors: Rosselin, Manon, Santo Domingo Mayoral, Jaime, Bermont, Flavien, Giacomello, Marta, Demaurex, Nicolas
Source: EMBO Rep
UVaDOC. Repositorio Documental de la Universidad de Valladolid
Universidad de Valladolid
EMBO Reports, Vol. 18, No 3 (2017) pp. 451-463
Publisher Information: Springer Science and Business Media LLC, 2017.
Publication Year: 2017
Subject Terms: Dynamins, 0301 basic medicine, membrane fusion, Gene Expression, Apoptosis, Dynamins/genetics/metabolism, Biosensing Techniques, bioenergetics, Membrane Potential, OPA1, Membrane Fusion, Mitochondrial Dynamics, GTP Phosphohydrolases, 03 medical and health sciences, Etoposide/pharmacology, Humans, ddc:612, GTP Phosphohydrolases/genetics/metabolism, Etoposide, Membrane Potential, Mitochondrial, 0303 health sciences, Mitochondria/drug effects/genetics/metabolism/ultrastructure, Articles, Hydrogen Peroxide, Hydrogen-Ion Concentration, mitoflash, HeLa Cells, Mitochondria, Mitochondrial Membranes, Proteolysis, Biochemistry, Molecular Biology, Genetics, Mitochondrial, Mitochondrial Membranes/metabolism, Hydrogen Peroxide/pharmacology
Description: 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.
Document Type: Article
Other literature type
File Description: application/pdf
Language: English
ISSN: 1469-3178
1469-221X
DOI: 10.15252/embr.201642931
Access URL: https://pubmed.ncbi.nlm.nih.gov/28174208
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331265
http://embor.embopress.org/content/18/3/451
http://embor.embopress.org/content/embor/18/3/451.full.pdf
https://www.ncbi.nlm.nih.gov/pubmed/28174208
https://www.embopress.org/doi/pdf/10.15252/embr.201642931
https://archive-ouverte.unige.ch/unige:100202/ATTACHMENT01
https://archive-ouverte.unige.ch/unige:100202
Rights: CC BY
Accession Number: edsair.doi.dedup.....68278526d97fb207f30846c0041c35db
Database: OpenAIRE
Description
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.
ISSN:14693178
1469221X
DOI:10.15252/embr.201642931