COX7A2L genetic variants determine cardiorespiratory fitness in mice and human

Published: 9 February 2023| Version 1 | DOI: 10.17632/8fcntj63x6.1
Giorgia Benegiamo


Mitochondrial respiratory complexes form superassembled structures called supercomplexes. We investigated the function of mitochondrial supercomplexes in human. COX7A2L is a supercomplex-specific assembly factor. By using human cis-eQTL data, we highlight a number of genetic variants in the COX7A2L gene that affect its expression in the muscle in a tissue specific manner. The most significant cis-eQTL is a 10 bp insertion in COX7A2L 3’UTR that increases mRNA expression by increasing mRNA stability. Human myotubes harbouring this insertion have higher supercomplexes and increased respiration. Importantly, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in human. We confirm these findings in mice: specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher VO2max, increased lean mass and increased energy expenditure. We further show that, in mice, Cox7a2l expression is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in human, and show that COX7A2L plays an important role in cardiorespiratory fitness. Enhancing cardiorespiratory fitness has broad therapeutic implications to reduce all-cause and cardiovascular mortality. This repository contains the scripts used to generate the figures in Benegiamo et al, "COX7A2L genetic variants determine cardiorespiratory fitness in mice and human"



Ecole Polytechnique Federale de Lausanne


Genetics, Cell Biology, Mitochondrion, Metabolism