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4303723 
Journal Article 
Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation 
Fazakerley, DJ; Minard, AY; Krycer, JR; Thomas, KC; Stöckli, J; Harney, DJ; Burchfield, JG; Maghzal, GJ; Caldwell, ST; Hartley, RC; Stocker, R; Murphy, MP; James, DE 
2018 
Yes 
Journal of Biological Chemistry
ISSN: 0021-9258
EISSN: 1083-351X 
293 
19 
7315-7328 
English 
29599292 
WOS:000432174500025 
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.