Opa1 relies on cristae preservation and ATP synthase to curtail reactive oxygen species accumulation in mitochondria

Reactive oxygen species (ROS) are a common product of active mitochondrial respiration carried in mitochondrial cristae, but whether cristae shape influences ROS levels is unclear. Here we report that the mitochondrial fusion and cristae shape protein Opa1 requires mitochondrial ATP synthase oligomers to reduce ROS accumulation. In cells fueled with galactose to force ATP production by mitochondria, cristae are enlarged, ATP synthase oligomers destabilized, and ROS accumulate. Opa1 prevents both cristae remodeling and ROS generation, without impinging on levels of mitochondrial antioxidant defense enzymes that are unaffected by Opa1 overexpression. Genetic and pharmacologic experiments indicate that Opa1 requires ATP synthase oligomerization and activity to reduce ROS levels upon a blockage of the electron transport chain. Our results indicate that the converging effect of Opa1 and mitochondrial ATP synthase on mitochondrial ultrastructure regulate ROS abundance to sustain cell viability.R.Q.-C was supported by an AIRC and a Fondazione Veronesi fellowship and by a H2020 Marie Sklodowska-Curie IEF GA793987. J.P.B. is funded by Agencia Estatal de Investigación (PID2019-105699RB-I00/AEI/10.13039/501100011033 and RED2018‐102576‐T), Instituto de Salud Carlos III (CB16/10/00282), Escalera de Excelencia CLU-2017-03, Ayudas Equipos Investigación Biomedicina 2017 Fundación BBVA and Fundación Ramón Areces. This work was supported by AIRC IG19991, Italian Ministry of Education, University and Research PRIN 2017BF3PXZ, Fondation Leducq TNE15004, Muscular Dystrophy Association (MDA USA) RG 603731 and Cariparo Foundation SIGMI (to L.S.)