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Elife. 2018 Feb 6;7. pii: e32111. doi: 10.7554/eLife.32111.

Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance.

Author information

1
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia.
2
School of Mathematics and Statistics, University of Sydney, Camperdown, Australia.
3
Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia.
4
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, United States.
5
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Australia.
6
Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Darlinghurst, Australia.
7
Genentech Inc., South San Francisco, United States.
8
Garvan Institute of Medical Research, Darlinghurst, Australia.
9
School of Biotechnology and Biomedical Sciences, University of New South Wales, Sydney, Australia.
10
St Vincent's Clinical School, University of New South Wales, Sydney, Australia.
11
Charles Perkins Centre, Sydney Medical School, University of Sydney, Camperdown NSW, Australia.
#
Contributed equally

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.

KEYWORDS:

Coenzyme Q; Insulin; Insulin resistance; Mitochondria; Oxidants; Ubiquinone; cell biology; human; human biology; medicine; mouse

Conflict of interest statement

DF, RC, PY, GM, KT, JK, SH, BP, KF, CM, NH, CD, JB, MC, WK, ZM, DC, DS, JG, KH, RS, DJ No competing interests declared, GK Employed by Genentech Inc. at the time the study was conducted. JY Jean YH Yang: Employed by Genentech Inc. at the time the study was conducted.

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