eLife (Feb 2018)
Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance
- Daniel J Fazakerley,
- Rima Chaudhuri,
- Pengyi Yang,
- Ghassan J Maghzal,
- Kristen C Thomas,
- James R Krycer,
- Sean J Humphrey,
- Benjamin L Parker,
- Kelsey H Fisher-Wellman,
- Christopher C Meoli,
- Nolan J Hoffman,
- Ciana Diskin,
- James G Burchfield,
- Mark J Cowley,
- Warren Kaplan,
- Zora Modrusan,
- Ganesh Kolumam,
- Jean YH Yang,
- Daniel L Chen,
- Dorit Samocha-Bonet,
- Jerry R Greenfield,
- Kyle L Hoehn,
- Roland Stocker,
- David E James
Affiliations
- Daniel J Fazakerley
- ORCiD
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia
- Rima Chaudhuri
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia
- Pengyi Yang
- School of Mathematics and Statistics, University of Sydney, Camperdown, Australia
- Ghassan J Maghzal
- Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia
- Kristen C Thomas
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia
- James R Krycer
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia
- Sean J Humphrey
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia
- Benjamin L Parker
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia
- Kelsey H Fisher-Wellman
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, United States
- Christopher C Meoli
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia
- Nolan J Hoffman
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia
- Ciana Diskin
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia
- James G Burchfield
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia
- Mark J Cowley
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Australia
- Warren Kaplan
- Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Darlinghurst, Australia
- Zora Modrusan
- Genentech Inc., South San Francisco, United States
- Ganesh Kolumam
- Genentech Inc., South San Francisco, United States
- Jean YH Yang
- School of Mathematics and Statistics, University of Sydney, Camperdown, Australia
- Daniel L Chen
- Garvan Institute of Medical Research, Darlinghurst, Australia
- Dorit Samocha-Bonet
- Garvan Institute of Medical Research, Darlinghurst, Australia
- Jerry R Greenfield
- Garvan Institute of Medical Research, Darlinghurst, Australia
- Kyle L Hoehn
- School of Biotechnology and Biomedical Sciences, University of New South Wales, Sydney, Australia
- Roland Stocker
- Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, Australia
- David E James
- ORCiD
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia; Charles Perkins Centre, Sydney Medical School, University of Sydney, Camperdown NSW, Australia
- DOI
- https://doi.org/10.7554/eLife.32111
- Journal volume & issue
-
Vol. 7
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
