biostudies-literatureBenegiamo GSwiss National Science FoundationEuropean Research Council1336-1351https://www.ebi.ac.uk/biostudies/studies/S-EPMC9584823biostudies-literatureUnknown4(10)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 COX7A2LNature metabolismCOX7A2L genetic variants determine cardiorespiratory fitness in mice and human.PMC9584823787702179435Laurila PPBenegiamo GEnriquez JACogliati SAuwerx JBrumpton BMRodriguez-Lopez SEriksson JGKlevjer MJha PBou Sleiman MBye AGoeminne LJEWohlwend MLahti JSalonen MKfalseCOX7A2L genetic variants determine cardiorespiratory fitness in mice and human.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 COX7A2L2022-01-01T00:00:00Z2022 Oct2026-05-28T01:20:39.282Z2025-04-06T12:10:37.52ZS-EPMC95848233625361810.1038/s42255-022-00655-0