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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.<\/jats:p>","DOI":"10.7554\/elife.32111","type":"journal-article","created":{"date-parts":[[2018,2,5]],"date-time":"2018-02-05T19:00:19Z","timestamp":1517857219000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.32111","source":"Crossref","is-referenced-by-count":126,"title":["Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance"],"prefix":"10.7554","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8241-2903","authenticated-orcid":true,"given":"Daniel J","family":"Fazakerley","sequence":"first","affiliation":[{"name":"Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, 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