Alteration of cardiolipin-dependent mitochondrial coupling in muscle protects against obesity

Alexandre Prola, et al.

Jul 29, 2019

Received Date: 10th July 19

Alexandre Prola, Jordan Blondelle, Aymeline Vandestienne, Jérôme Piquereau, Raphaël GP Denis, Stéphane Guyot, Hadrien Chauvin, Arnaud Mourier, Martine Letheule, Marie Maurer, Céline Henry, Nahed Khadhraoui, Guillaume Courtin, Nicolas Blanchard-Gutton, Laurent Guillaud, Inès Barthélémy, Mélanie Gressette, Audrey Solgadi, Florent Dumont, Julien Castel, Julien Ternacle, Jean Demarquoy, Alexandra Malgoyre, Nathalie Koulmann, Geneviève Derumeaux, Marie-France Giraud, Stéphane Blot, Frédéric Joubert, Vladimir Veksler, Serge Luquet, Frédéric Relaix, Laurent Tiret and Fanny Pilot-Storck

The tubular shape of mitochondrial cristae depends upon a specific composition of the inner mitochondrial membrane, including cardiolipin that allows strong curvature and promotes optimal organization of ATP synthase. Here we identify Hacd1, which encodes an enzyme involved in very long chain fatty acid biosynthesis, as a key regulator of composition, structure and functional properties of mitochondrial membranes in muscle. In Hacd1-deficient mice, the reduced cardiolipin content was associated with dilation of cristae and caused defective phosphorylating respiration, characterized by absence of proton leak and oxidative stress.

The skeletal muscle-specific mitochondrial coupling defect produced a global elevation in basal energy expenditure with increased carbohydrate and lipid catabolism, despite decreased muscle mass and locomotor capacities. Mice were protected against diet-induced obesity despite reduced muscle activity, providing an in vivo proof of concept that reducing mitochondrial coupling efficiency in skeletal muscle might be an actionable mechanism in metabolic disease conditions.

Read in full at bioRxiv.

This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature