Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle
Alexandre Prola, Jordan Blondelle, Aymeline Vandestienne, Jérôme Piquereau, R Denis, Stéphane Guyot, Hadrien Chauvin, Arnaud Mourier, Marie Maurer, Céline Henry, Nahed Khadhraoui, Cindy Gallerne, Thibaut Molinié, Guillaume Courtin, Laurent Guillaud, Mélanie Gressette, Audrey Solgadi, Florent Dumont, Julien Castel, Julien Ternacle, Jean Demarquoy, Alexandra Malgoyre, Nathalie Koulmann, Geneviève Dérumeaux, Marie‐France Giraud, F. Joubert, Vladimir Veksler, Serge Luquet, Frédéric Relaix, Laurent Tiret, Fanny Pilot‐Storck
Abstract
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.