Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation

被引:116
作者
Fazakerley, Daniel J. [1 ]
Minard, Annabel Y. [1 ,7 ]
Krycer, James R. [1 ]
Thomas, Kristen C. [1 ]
Stockli, Jacqueline [1 ]
Harney, Dylan. J. [1 ]
Burchfield, James G. [1 ]
Maghzal, Ghassan J. [3 ,4 ]
Caldwell, Stuart T. [5 ]
Hartley, Richard C. [5 ]
Stocker, Roland [3 ,4 ]
Murphy, Michael P. [6 ]
James, David E. [1 ,2 ]
机构
[1] Univ Sydney, Sch Life & Environm Sci, Charles Perkins Ctr, Camperdown, NSW 2006, Australia
[2] Univ Sydney, Sydney Med Sch, Charles Perkins Ctr, Camperdown, NSW 2006, Australia
[3] Victor Chang Cardiac Res Inst, Vasc Biol Div, Darlinghurst, NSW 2010, Australia
[4] Univ New South Wales, St Vincents Clin Sch, Sydney, NSW 2052, Australia
[5] Univ Glasgow, Sch Chem, Glasgow G12 8QQ, Lanark, Scotland
[6] Univ Cambridge, MRC Mitochondrial Biol Unit, Hills Rd, Cambridge CB2 0XY, England
[7] Univ Iowa, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA
基金
英国医学研究理事会; 英国惠康基金; 澳大利亚国家健康与医学研究理事会;
关键词
superoxide ion; oxidative stress; hydrogen peroxide; mitochondria; insulin resistance; insulin; adipocyte; muscle; adipose tissue; Mitochondrial dysfunction; ACTIVATED PROTEIN-KINASE; MANGANESE SUPEROXIDE-DISMUTASE; SKELETAL-MUSCLE; IN-VIVO; GLUCOSE-UPTAKE; COMPLEX-III; MICE; FAT; OBESITY; GLUT4;
D O I
10.1074/jbc.RA117.001254
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 m, 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.
引用
收藏
页码:7315 / 7328
页数:14
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