bims-resufa 2022-10-23 papers

Issue of 2022–10–23
two papers selected by
Vera Strogolova, Strong Microbials, Inc

Nat Metab. 2022 Oct;4(10): 1336-1351

COX7A2L genetic variants determine cardiorespiratory fitness in mice and human.

Giorgia Benegiamo, Maroun Bou Sleiman, Martin Wohlwend, Sandra Rodríguez-López, Ludger J E Goeminne, Pirkka-Pekka Laurila, Marie Klevjer, Minna K Salonen, Jari Lahti, Pooja Jha, Sara Cogliati, José Antonio Enriquez, Ben M Brumpton, Anja Bye, Johan G Eriksson, Johan Auwerx.

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.

DOI: https://doi.org/10.1038/s42255-022-00655-0

Elife. 2022 Oct 18. pii: e78915. [Epub ahead of print]11

Tissue-specific mitochondrial HIGD1C promotes oxygen sensitivity in carotid body chemoreceptors.

Alba Timón-Gómez, Alexandra L Scharr, Nicholas Y Wong, Erwin Ni, Arijit Roy, Min Liu, Julisia Chau, Jack L Lampert, Homza Hireed, Noah S Kim, Masood Jan, Alexander R Gupta, Ryan W Day, James M Gardner, Richard J A Wilson, Antoni Barrientos, Andy J Chang.

Mammalian carotid body arterial chemoreceptors function as an early warning system for hypoxia, triggering acute life-saving arousal and cardiorespiratory reflexes. To serve this role, carotid body glomus cells are highly sensitive to decreases in oxygen availability. While the mitochondria and plasma membrane signaling proteins have been implicated in oxygen sensing by glomus cells, the mechanism underlying their mitochondrial sensitivity to hypoxia compared to other cells is unknown. Here, we identify HIGD1C, a novel hypoxia-inducible gene domain factor isoform, as an electron transport chain Complex IV-interacting protein that is almost exclusively expressed in the carotid body and is therefore not generally necessary for mitochondrial function. Importantly, HIGD1C is required for carotid body oxygen sensing and enhances Complex IV sensitivity to hypoxia. Thus, we propose that HIGD1C promotes exquisite oxygen sensing by the carotid body, illustrating how specialized mitochondria can be used as sentinels of metabolic stress to elicit essential adaptive behaviors.

Keywords: biochemistry; chemical biology; human; mouse; neuroscience; rat

DOI: https://doi.org/10.7554/eLife.78915