2026-06-14T03:46:18Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/158162024-09-27T09:23:48Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Benegiamo, Giorgia author Bou Sleiman, Maroun author Wohlwend, Martin author Rodríguez-López, Sandra author Goeminne, Ludger J E author Laurila, Pirkka-Pekka author Klevjer, Marie author Salonen, Minna K author Lahti, Jari author Jha, Pooja author Cogliati, Sara author Enriquez, Jose Antonio author Brumpton, Ben M author Bye, Anja author Eriksson, Johan G author Auwerx, Johan author 2022-10 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 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. Nat Metab. 2022 Oct;4(10):1336-1351. 10.1038/s42255-022-00655-0 2522-5812 Nature metabolism 36253618 http://hdl.handle.net/20.500.12105/15816 COX7A2L genetic variants determine cardiorespiratory fitness in mice and human.