bims-cytox1 2022-10-23 papers

Life Sci Alliance. 2023 Jan;pii: e202201526. [Epub ahead of print]6(1):

The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import.

Saskia Rödl, Fabian den Brave, Markus Räschle, Büsra Kizmaz, Svenja Lenhard, Carina Groh, Hanna Becker, Jannik Zimmermann, Bruce Morgan, Elke Richling, Thomas Becker, Johannes M Herrmann.

Mitochondria play a key role in cellular energy metabolism. Transitions between glycolytic and respiratory conditions induce considerable adaptations of the cellular proteome. These metabolism-dependent changes are particularly pronounced for the protein composition of mitochondria. Here, we show that the yeast cytosolic ubiquitin conjugase Ubc8 plays a crucial role in the remodeling process when cells transition from respiratory to fermentative conditions. Ubc8 is a conserved and well-studied component of the catabolite control system that is known to regulate the stability of gluconeogenic enzymes. Unexpectedly, we found that Ubc8 also promotes the assembly of the translocase of the outer membrane of mitochondria (TOM) and increases the levels of its cytosol-exposed receptor subunit Tom22. Ubc8 deficiency results in compromised protein import into mitochondria and reduced steady-state levels of mitochondrial proteins. Our observations show that Ubc8, which is controlled by the prevailing metabolic conditions, promotes the switch from glucose synthesis to glucose usage in the cytosol and induces the biogenesis of the mitochondrial TOM machinery to improve mitochondrial protein import during phases of metabolic transition.

DOI: https://doi.org/10.26508/lsa.202201526

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

FASEB J. 2022 Nov;36(11): e22600

Tipping the balance toward stemness in trophoblast: Metabolic programming by Cox6B2.

Sarbani Saha, Rumela Bose, Shreeta Chakraborty, Rupasri Ain.

Metabolic effector(s) driving cell fate is an emerging concept in stem cell biology. Here we showed that Cytochrome C Oxidase Subunit 6B2 (Cox6B2) is essential to maintain the stemness of trophoblast stem (TS) cells. RNA interference of Cox6b2 resulted in decreased mitochondrial Complex IV activity, ATP production, and oxygen consumption rate in TS cells. Furthermore, depletion of Cox6b2 in TS cells led to decreased self-renewal capacity indicated by compromised BrdU incorporation, Ki67 staining, and decreased expression of TS cell genetic markers. As expected, the consequence of Cox6b2 knockdown was the induction of differentiation. TS cell stemness factor CDX2 transactivates Cox6b2 promoter in TS cells. In differentiated cells, Cox6b2 is post-transcriptionally regulated by two microRNAs, miR-322-5p and miR-503-5p, leading to its downregulation as demonstrated by the gain-in or loss of function of these miRNAs. Cox6b2 transcripts gradually rise in placental trophoblast gestation progresses in both mice and rats with predominant expression in labyrinthine trophoblast. Cox6b2 expression is compromised in the growth-restricted placenta of rats with reciprocal up-regulation of miR-322-5p and miR-503-5p. These data highlight the importance of Cox6B2 in the regulation of TS cell state and uncompromised placental growth.

Keywords: CDX2; differentiation; miRNA; mitochondria; self-renewal; stem cell

DOI: https://doi.org/10.1096/fj.202200703RR