Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation.
Authors
Minard, Annabel Y
Krycer, James R
Thomas, Kristen C
Stöckli, Jacqueline
Harney, Dylan J
Burchfield, James G
Maghzal, Ghassan J
Caldwell, Stuart T
Hartley, Richard C
Stocker, Roland
James, David E
Publication Date
2018-05-11Journal Title
J Biol Chem
ISSN
0021-9258
Publisher
Elsevier BV
Volume
293
Issue
19
Pages
7315-7328
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Fazakerley, D., Minard, A. Y., Krycer, J. R., Thomas, K. C., Stöckli, J., Harney, D. J., Burchfield, J. G., et al. (2018). Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation.. J Biol Chem, 293 (19), 7315-7328. https://doi.org/10.1074/jbc.RA117.001254
Abstract
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 because 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; a more profound effect on glucose transport than on other insulin-regulated processes, such as protein synthesis and lipolysis; an absence of overt defects in insulin signaling; 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.
Keywords
3T3-L1 Cells, Mitochondria, Adipocytes, Myoblasts, Animals, Mice, Inbred C57BL, Mice, Insulin Resistance, Hydrogen Peroxide, Superoxides, Paraquat, Insulin, Adenylate Kinase, Glucose, Protein Isoforms, Herbicides, Electron Transport, Oxidative Phosphorylation, Oxygen Consumption, Male, Glucose Transporter Type 4, Peroxiredoxins
Sponsorship
Medical Research Council (MC_UU_00015/3)
Wellcome Trust (110159/Z/15/Z)
Medical Research Council (MC_U105663142)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1074/jbc.RA117.001254
This record's URL: https://www.repository.cam.ac.uk/handle/1810/277619
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