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.

Mitochondrial Cristae Architecture and Functions: Lessons from Minimal Model Systems

“…The presence of CL at a higher extent in the cristae lumen leaflet as demonstrated by in vitro systems and predicted by in silico studies, can directly affect the functioning of the OXPHOS process independently on their effect on OXPHOS protein activity. In a recent study, Prola et al [ 23 ] showed that in a CL-deficient mice induced by the mutation of the HACD1 gene, cristae shape was altered, and a reduced coupling efficiency in the respiratory chain (diminution of the yield of ATP produced by oxygen consumed) was observed, with no change in respiratory chain complex activity and in proton gradient formation. The addition of CL to isolated mitochondria from Hacd1 -KO mice (by fusing with CL liposomes) rescued their coupling efficiency, pointed out the specific role of CL content in the efficiency of OXPHOS process.…”

“…The IMM morphology and organization are crucial for the assembly and proper function of the enzymes involved in OXPHOS process, as well as in the establishment of the proton gradient [ 4 , 5 ]. It was also shown that cristae shape and number can change depending on energy requirement [ 1 , 2 , 20 ] while, in different pathologies, alteration of mitochondrial function is most of the time associated with cristae destructuration [ 21 , 22 , 23 ]. This strongly suggests that a structure-function relationship exist at the cristae level.…”

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

“…This is probably why CL binds to the F 1 F 0 ATP synthase with higher affinity than all other mitochondrial phospholipids [ 235 ]. ATP synthesis could be significantly enhanced when proton translocation is increased by the non-bilayer structures at the apex of IMM cristae formed during CL interactions with the F 0 section of ATP synthase [ 236 ], whereas CL deficiency can result in compromised mitochondrial energetic and coupling efficiency in skeletal muscles [ 237 ]. Mitochondrial bioenergetics are heavily dependent upon optimal CL lipid composition, content, and structure [ 238 ]; therefore, mitochondrial dysfunction as a result of CL peroxidation and depletion is associated with numerous pathophysiological conditions [ 239 ], including myocardial ischemia [ 240 ], nonalcoholic fatty liver disease [ 241 ], thyroid dysfunctions [ 242 ], diabetes, obesity and other metabolic diseases [ 243 , 244 ], cancer [ 245 ], as well as a wide range of neurological disorders including Alzheimer’s disease [ 246 ], Parkinson’s disease [ 247 , 248 ], amyotrophic lateral sclerosis [ 249 ], Barth syndrome [ 250 , 251 ], and traumatic brain injury [ 252 , 253 ].…”

Phospholipids: Identification and Implication in Muscle Pathophysiology

“…For example, pathogenic variants of HACD1 (3-hydroxyacyl-CoA dehydratase 1), an ER resident enzyme involved in the synthesis of very long-chain fatty acids, have been associated with congenital myopathies in humans and in dogs [ 90 , 91 , 139 ]. In Hacd1-deficient mice, skeletal muscle mitochondria exhibit a significant decrease in CL content in the mitochondrial inner membrane [ 91 ]. This is associated with important cristae remodeling and strong alterations of mitochondrial coupling, leading to a higher energy dissipation.…”