Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle

Prola, Alexandre; Blondelle, Jordan; Vandestienne, Aymeline; Piquereau, Jérôme; Denis, Raphaël G. P.; Guyot, Stéphane; Chauvin, Hadrien; Mourier, Arnaud; Maurer, Marie; Henry, Céline; Khadhraoui, Nahed; Gallerne, Cindy; Molinié, Thibaut; Courtin, Guillaume; Guillaud, Laurent; Gressette, Mélanie; Solgadi, Audrey; Dumont, Florent; Castel, Julien; Ternacle, Julien; Demarquoy, Jean; Malgoyre, Alexandra; Koulmann, Nathalie; Derumeaux, Geneviève; Giraud, Marie-France; Joubert, Frédéric; Veksler, Vladimir; Luquet, Serge; Relaix, Frédéric; Tiret, Laurent; Pilot-Storck, Fanny

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.