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Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance
Open accessAbstract
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.
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“Given the well-established potential for oxidative stress and consequent oxidative damage to drive insulin resistance (11–18), we reasoned that the development of insulin resistance in the sedentary aged mice may be attributed to decreased NOX4 abundance or activity.”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [15]
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“Obesity is associated with systemic oxidative stress (43, 44), which promotes insulin resistance (11–18).”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [15]
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Metadata
- 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.
- Affiliations
- The University of Sydney (AU)
- Victor Chang Cardiac Research Institute (AU)
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, United States
- Garvan Institute of Medical Research (AU)
- Genentech (US)
- School of Mathematics and Statistics, University of Sydney, Camperdown, Australia
- Garvan Institute of Medical Research, Darlinghurst, Australia
- UNSW Sydney (AU)
- Corresponding author
- Stocker, Roland
- James, David E
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2018-02-06
- Volume
- 7
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5800848
- OpenAlex
- W2785501834
- Cited by
- 160
- References
- 94
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 17 · 2023: 24 · 2022: 14 · 2021: 37 · 2020: 16 · 2019: 20 · 2018: 9
- FWCI
- 7.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Research Bank (Australian Catholic University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome (092255/Z/10/Z)
- National Health and Medical Research Council (1052616, 1086850, 1061122)
- Australian Research Council (DP150102408)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- insulin resistance, adipose tissue, skeletal muscle, superoxide, hydrogen peroxide, succinate dehydrogenase, metabolic disorders
- MeSH terms
- Adipose Tissue, Animals, Ataxia, Humans, Insulin Resistance, Mitochondria, Muscles, Sensitivity and Specificity, Ubiquinone, Oxidants, Adipocytes, Muscle Weakness, Mitochondrial Diseases, Mice
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