The cristae modulator Optic atrophy 1 requires mitochondrial ATP synthase oligomers to safeguard mitochondrial function

• Published in: Nature communications Vol. 9; no. 1; pp. 3399 - 13
• Main Authors: Quintana-Cabrera, Rubén, Quirin, Charlotte, Glytsou, Christina, Corrado, Mauro, Urbani, Andrea, Pellattiero, Anna, Calvo, Enrique, Vázquez, Jesús, Enríquez, José Antonio, Gerle, Christoph, Soriano, María Eugenia, Bernardi, Paolo, Scorrano, Luca
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.08.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/2; 13/89; 14/34; 14/35; 14/63; 38; 631/80/642/333/1465; 631/80/82/23; 82/29; 96/106; Animals; Antimycin A - pharmacology; ATP; ATP synthase; Atrophy; Cell Survival - drug effects; Chains; Corrosion inhibitors; Cristae; Dimerization; Electrochemistry; Electron transport; Electrophoresis, Polyacrylamide Gel; Fusion protein; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Humanities and Social Sciences; Immunoblotting; Immunoprecipitation; Liposomes; Mice; Microscopy, Electron, Transmission; Mitochondria; Mitochondria - metabolism; Mitochondrial DNA; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mitochondrial Proton-Translocating ATPases - genetics; Mitochondrial Proton-Translocating ATPases - metabolism; multidisciplinary; Oligomerization; Oligomers; Oligomycin; Optic atrophy; Proteins; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05655-x

It is unclear how the mitochondrial fusion protein Optic atrophy 1 (OPA1), which inhibits cristae remodeling, protects from mitochondrial dysfunction. Here we identify the mitochondrial F 1 F o -ATP synthase as the effector of OPA1 in mitochondrial protection. In OPA1 overexpressing cells, the loss of proton electrochemical gradient caused by respiratory chain complex III inhibition is blunted and this protection is abolished by the ATP synthase inhibitor oligomycin. Mechanistically, OPA1 and ATP synthase can interact, but recombinant OPA1 fails to promote oligomerization of purified ATP synthase reconstituted in liposomes, suggesting that OPA1 favors ATP synthase oligomerization and reversal activity by modulating cristae shape. When ATP synthase oligomers are genetically destabilized by silencing the key dimerization subunit e , OPA1 is no longer able to preserve mitochondrial function and cell viability upon complex III inhibition. Thus, OPA1 protects mitochondria from respiratory chain inhibition by stabilizing cristae shape and favoring ATP synthase oligomerization. Mitochondrial cristae shape influences apoptosis and respiration. Here the authors show that the mitochondrial fusion protein OPA1 protects mitochondria from dysfunction by promoting ATP synthase oligomerization and reversal activity.