Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle

A. Prola , J. Blondelle , A. Vandestienne , J. Piquereau , R. Denis , S. Guyot , H. Chauvin , A. Mourier , M. Maurer , C. Henry , N. Khadhraoui , C. Gallerne , T. Molinié , G. Courtin , L. Guillaud , M. Gressette , A. Solgadi , F. Dumont , J. Castel , J. Ternacle , J. Demarquoy , A. Malgoyre , N. Koulmann , G. Derumeaux , M.F. Giraud , F. Joubert , V. Veksler , S. Luquet , F. Relaix , L. Tiret , F. Pilot-Storck

Science Advances, 7, 1, eabd6322
Published 01 Jan. 2021


Unbalanced energy partitioning participates in the rise of obesity, a major public health concern in many countries. Increasing basal energy expenditure has been proposed as a strategy to fight obesity yet raises efficiency and safety concerns. Here, we show that mice deficient for a muscle-specific enzyme of very-long-chain fatty acid synthesis display increased basal energy expenditure and protection against high-fat diet-induced obesity. Mechanistically, muscle-specific modulation of the very-long-chain fatty acid pathway was associated with a reduced content of the inner mitochondrial membrane phospholipid cardiolipin and a blunted coupling efficiency between the respiratory chain and adenosine 5'-triphosphate (ATP) synthase, which was restored by cardiolipin enrichment. Our study reveals that selective increase of lipid oxidative capacities in skeletal muscle, through the cardiolipin-dependent lowering of mitochondrial ATP production, provides an effective option against obesity at the whole-body level.