| Literature DB >> 29402381 |
Roland Stocker1,2, David E James3,4, Daniel J Fazakerley3, Rima Chaudhuri3, Pengyi Yang5, Ghassan J Maghzal1, Kristen C Thomas3, James R Krycer3, Sean J Humphrey3, Benjamin L Parker3, Kelsey H Fisher-Wellman6, Christopher C Meoli3, Nolan J Hoffman3, Ciana Diskin3, James G Burchfield3, Mark J Cowley7, Warren Kaplan8, Zora Modrusan9, Ganesh Kolumam9, Jean Yh Yang5, Daniel L Chen10, Dorit Samocha-Bonet10, Jerry R Greenfield10, Kyle L Hoehn11.
Abstract
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.Entities:
Keywords: Coenzyme Q; Insulin; Insulin resistance; Mitochondria; Oxidants; Ubiquinone; cell biology; human; human biology; medicine; mouse
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Year: 2018 PMID： 29402381 PMCID： PMC5800848 DOI： 10.7554/eLife.32111
Source DB: PubMed Journal: Elife ISSN： 2050-084X Impact factor: 8.140