Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance
Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance.
|ISBN||2050-084X (Electronic) 2050-084X (Linking)|
|Authors||Fazakerley, D. J.; Chaudhuri, R.; Yang, P.; Maghzal, G. J.; Thomas, K. C.; Krycer, J. R.; Humphrey, S. J.; Parker, B. L.; Fisher-Wellman, K. H.; Meoli, C. C.; Hoffman, N. J.; Diskin, C.; Burchfield, J. G.; Cowley, M. J.; Kaplan, W.; Modrusan, Z.; Kolumam, G.; Yang, J. Y.; Chen, D. L.; Samocha-Bonet, D.; Greenfield, J. R.; Hoehn, K. L.; Stocker, R.; James, D. E.|
|Responsible Garvan Author|
|Published Pages||pii: e32111|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/29402381|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/14499|