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Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle.

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.

SUBMITTER: Prola A

PROVIDER: S-EPMC7775760 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle.

Prola Alexandre A Blondelle Jordan J Vandestienne Aymeline A Piquereau Jérôme J Denis Raphaël G P RGP Guyot Stéphane S Chauvin Hadrien H Mourier Arnaud A Maurer Marie M Henry Céline C Khadhraoui Nahed N Gallerne Cindy C Molinié Thibaut T Courtin Guillaume G Guillaud Laurent L Gressette Mélanie M Solgadi Audrey A Dumont Florent F Castel Julien J Ternacle Julien J Demarquoy Jean J Malgoyre Alexandra A Koulmann Nathalie N Derumeaux Geneviève G Giraud Marie-France MF Joubert Frédéric F Veksler Vladimir V Luquet Serge S Relaix Frédéric F Tiret Laurent L Pilot-Storck Fanny F

Science advances 20210101 1

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 ...[more]

PMID: 33523852

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Project description:Emerging evidence indicates that mitochondria are locally coupled to endoplasmic reticulum (ER) Ca2+ release in myoblasts and to sarcoplasmic reticulum (SR) Ca2+ release in differentiated muscle fibers in order to regulate cytoplasmic calcium dynamics and match metabolism with cell activity. However, the mechanism of the developmental transition from ER to SR coupling remains unclear. We have studied mitochondrial sensing of IP3 receptor (IP3R)- and ryanodine receptor (RyR)-mediated Ca2+ signals in H9c2 myoblasts and differentiating myotubes, as well as the attendant changes in mitochondrial morphology. Mitochondria in myoblasts were largely elongated, luminally connected and relatively few in number, whereas the myotubes were densely packed with globular mitochondria that displayed limited luminal continuity. Vasopressin, an IP3-linked agonist, evoked a large cytoplasmic Ca2+ ([Ca2+]c) increase in myoblasts, whereas it elicited a smaller response in myotubes. Conversely, RyR-mediated Ca2+ release induced by caffeine, was not observed in myoblasts, but triggered a large [Ca2+]c signal in myotubes. Both the IP3R and the RyR-mediated [Ca2+]c rise was closely associated with a mitochondrial matrix Ca2+ ([Ca2+]m) signal. Every myotube that showed a [Ca2+]c spike also displayed a [Ca2+]m response. Addition of IP3 to permeabilized myoblasts and caffeine to permeabilized myotubes also resulted in a rapid [Ca2+]m rise, indicating that Ca2+ was delivered via local coupling of the ER/SR and mitochondria. Thus, as RyRs are expressed during muscle differentiation, the local connection between RyR and mitochondrial Ca2+ uptake sites also appears. When RyR1 was exogenously introduced to myoblasts by overexpression, the [Ca2+]m signal appeared together with the [Ca2+]c signal, however the mitochondrial morphology remained unchanged. Thus, RyR expression alone is sufficient to induce the steps essential for their alignment with mitochondrial Ca2+ uptake sites, whereas the mitochondrial proliferation and reshaping utilize either downstream or alternative pathways.

Dataset Information

Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle.

Publications

Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle.

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