COX7A2L genetic variants determine cardiorespiratory fitness in mice and human

Abstract

Mitochondrial respiratory complexes form superassembled structures called supercomplexes. COX7A2L is a supercomplex-specific assembly factor in mammals, although its implication for supercomplex formation and cellular metabolism remains controversial. Here we identify a role for COX7A2L for mitochondrial supercomplex formation in humans. By using human cis-expression quantitative trait loci data, we highlight genetic variants in the COX7A2L gene that affect its skeletal muscle expression specifically. The most significant cis-expression quantitative trait locus is a 10-bp insertion in the COX7A2L 3′ untranslated region that increases messenger RNA stability and expression. Human myotubes harboring this insertion have more supercomplexes and increased respiration. Notably, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in humans. Accordingly, specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher maximal oxygen consumption, increased lean mass and increased energy expenditure. Furthermore, Cox7a2l expression in mice is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in humans and show that COX7A2L plays an important role in cardiorespiratory fitness, which could have broad therapeutic implications in reducing cardiovascular mortality.

Unbiased complexome profiling and global proteomics analysis reveals mitochondrial impairment and potential changes at the intercalated disk in presymptomatic R14Δ/+mice hearts

“…To-date, two proteins have been identified to play a critical role in RSC assembly: NDUFAB1 61,64,65 and COX7A2L 66,67 . Loss of either has been shown to reduce mitochondria efficiency and increase ROS production 61,68 . Interestingly, expression of both of these assembly factors was significantly reduced in R14 Δ/+ mice (Figure 6c), which may underlie the observed changes in RSC composition.…”

Impairment of adrenergically-regulated thermogenesis in brown fat of obesity-resistant mice is compensated by non-shivering thermogenesis in skeletal muscle

“…In accordance with these data, we found very low levels of COX7R/SCAFI protein and of CIII 2 CIV respiratory supercomplexes in the muscle of B6 compared to AJ mice thus confirming that COX7R/SCAFI is essential for Q-respirasome (CIII 2 CIV) formation. In contrast, N-respirasome supercomplexes (CICIII 2 CIV, reviewed in [ 88 ]) can assemble also with COX7A2 or COX7A1 subunits [ 27 , 93 ] and N-respirasome structural and functional organisation depends on prevalent COX7A isoform [ 27 ]. COX7R/SCAFI associated formation of Q-respirasome even led to a decrease in the content of N-respirasome in muscle of AJ compared to B6, which could improve oxidation of flavoprotein-dependent substrates and accordingly, the utilization of FA [ 82 , 88 ].…”

“…Previous studies in mice demonstrated possible metabolic role of COX7R/SCAFI and its importance in modulation of muscle exercise performance [ 83 , 89 ], fat accumulation [ 83 ], body growth and fertility [ 94 ], or blood glucose levels [ 95 ]. Finally, the recent study [ 93 ] demonstrated that reconstitution of functional COX7R/SCAFI in B6 mice increased both energy expenditure and lean mass of the animals, and that polymorphism in COX7R/SCAFI gene was linked with adiposity and cardiorespiratory fitness in humans. Overall, the data indicate that expression of COX7R/SCAFI may support the strain-specific adaptive induction of NST by CA in skeletal muscle.…”

Discovering Novel Prognostic Biomarkers of Hepatocellular Carcinoma using eXplainable Artificial Intelligence

“…Cytochrome C Oxidase Subunit 7A2 Like (COX7A2L) is a nuclear DNA-encoded gene involved in the assembly of mitochondrial respiratory chain through binding complex III that stabilizes the III2+IV supercomplex ( 45 ). Increased COX7A2L expression in the muscle has been associated with lower body fat and improved cardiorespiratory fitness in humans ( 46 ). Interestingly, such overexpression was also shown to promote tumor growth and metastasis by inducing ROS production in HCC cells ( 47 ).…”