COX7A2L genetic variants determine cardiorespiratory fitness in mice and human

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"

线粒体呼吸复合物（mitochondrial respiratory complexes）可形成超组装结构，即超复合物（supercomplexes）。本研究针对人类线粒体超复合物的功能开展系统性探究。COX7A2L基因是一种超复合物特异性组装因子。本研究通过人类顺式作用表达数量性状位点（cis-eQTL）数据，鉴定出COX7A2L基因中多个以组织特异性方式调控其肌肉表达的遗传变异。其中最显著的顺式作用eQTL为COX7A2L基因3'非翻译区（3’UTR）的一处10bp插入变异，该变异通过提升mRNA稳定性上调其转录表达水平。携带该插入变异的人类肌管中，超复合物丰度更高，细胞呼吸功能亦显著增强。值得关注的是，人类肌肉组织中COX7A2L基因表达上调与体脂率降低及心肺耐力提升呈显著正相关。我们在C57BL/6J小鼠模型中验证了上述研究结论：在其肌肉组织中特异性重建Cox7a2l基因表达，可提升小鼠的最大摄氧量（VO2max）、增加瘦体重并提高能量消耗。本研究还进一步证实，在小鼠体内，运动可特异性诱导肌肉组织中Cox7a2l基因的表达。上述研究结果阐明了人类线粒体超复合物形成与功能的遗传基础，并证实COX7A2L基因对心肺耐力具有关键调控作用。提升心肺耐力对于降低全因死亡率与心血管疾病死亡率具有广泛的临床转化价值与治疗意义。本数据集仓库包含用于生成Benegiamo等人发表论文《COX7A2L遗传变异决定小鼠与人类心肺耐力》中所有图表的代码脚本。