Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation

Fazakerley, D. J. et al. (2018) Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation. Journal of Biological Chemistry, 293(19), pp. 7315-7328. (doi: 10.1074/jbc.RA117.001254) (PMID:29599292) (PMCID:PMC5950018)

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Mitochondrial oxidative stress, mitochondrial dysfunction, or both have been implicated in insulin resistance. However, disentangling the individual roles of these processes in insulin resistance has been difficult since they often occur in tandem and tools that selectively increase oxidant production without impairing mitochondrial respiration have been lacking. Using the dimer:monomer status of peroxiredoxin isoforms as an indicator of compartmental hydrogen peroxide burden, we provide evidence that oxidative stress is localized to mitochondria in insulin resistant 3T3-L1 adipocytes and adipose tissue from mice. To dissociate oxidative stress from impaired oxidative phosphorylation and study whether mitochondrial oxidative stress per se can cause insulin resistance we used mitochondria-targeted paraquat (MitoPQ) to generate superoxide within mitochondria without directly disrupting the respiratory chain. At ≤ 10 µM, MitoPQ specifically increased mitochondrial superoxide and hydrogen peroxide without altering mitochondrial respiration in intact cells. Under these conditions, MitoPQ impaired insulin-stimulated glucose uptake and glucose transporter 4 (GLUT4) translocation to the plasma membrane in both adipocytes and myotubes. MitoPQ recapitulated many features of insulin resistance found in other experimental models including: increased oxidants in mitochondria but not cytosol; more profound effect on glucose transport than other insulin-regulated processes such as protein synthesis and lipolysis; absence of overt defects in insulin signalling; and defective insulin- but not AMP-activated protein kinase (AMPK)-regulated GLUT4 translocation. We conclude that elevated mitochondrial oxidants rapidly impair insulin-regulated GLUT4 translocation and significantly contribute to insulin resistance and that MitoPQ is an ideal tool for studying the link between mitochondrial oxidative stress and regulated GLUT4 trafficking.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Caldwell, Dr Stuart and Hartley, Professor Richard
Authors: Fazakerley, D. J., Minard, A. Y., Krycer, J. R., Thomas, K. C., Stöckli, J., Harney, D. J., Burchfield, J. G., Maghzal, G. J., Caldwell, S. T., Hartley, R. C., Stocker, R., Murphy, M. P., and James, D. E.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN (Online):1083-351X
Published Online:29 March 2018
Copyright Holders:Copyright © 2018 The American Society for Biochemistry and Molecular Biology, Inc.
First Published:First published in Journal of Biological Chemistry 293(19):7315-7328
Publisher Policy:Reproduced under a Creative Commons License

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