S and A.A. performed and supervised in vitro experiments in cell/astrocyte cultures and ex vivo analysis of brain tissue; A.B.G, C.I. and P.G.S. performed behavioral experiments and surgical procedures in mice; E.R. and M.G. provided some CB1-KO mice to the group of J.P.B.; D.A and A.P. performed electrophysiological experiments not shown in the manuscript; M.V. and F.J.K performed mouse perfusion and immunohistochemistry experiments; A.C. and L.B. produced some of the viral constructs used (e.g. Syn-mitoCAT); I.B.R, N.P., S.A. and P.G. performed and supervised electron microscopy experiments; M.L.L.R. provided pharmacological tools (HU-Biot); C.J., N.D and L.P provided specific viral constructs to modulate the MCT-2 transporter; C.J. and G.B. provided data and viral vectors regarding mouse retro-orbital injections; B.L and P.V.P. provided important conceptual ideas; A.K.B.S performed in vivo NMR experiments.

No abstract

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.