Mitochondrial CoQ deficiency drives insulin resistance by increasing mitochondrial oxidants
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW, Australia.
- School of Mathematics and Statistics, University of Sydney, Camperdown, NSW, Australia.
- Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
- Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia.
- MRC Mitochondrial Biology Unit, Hills Road, University of Cambridge, Cambridge, UK.
- St Vincent’s Clinical School, University of New South Wales, Sydney, Australia.
- Charles Perkins Centre, Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.
Insulin resistance in muscle, adipose and liver tissue is a gateway to a number of metabolic diseases including type 2 diabetes. Alterations in several facets of mitochondrial biology are implicated in insulin resistance including impaired oxidative phosphorylation and increased mitochondrial reactive oxygen species (ROS). However, disentangling the respective roles of these processes in insulin resistance has been difficult since they often occur in tandem. We have used a new small molecule (mitochondria-targeted paraquat) to acutely generate superoxide within mitochondria, without disrupting the respiratory chain, to show that mitochondrial oxidants alone are sufficient to induce insulin resistance. Increased ROS, specifically in mitochondria, are a common feature of an array of in vitro and in vivo models of insulin resistance, yet the drivers of mitochondrial ROS under these conditions are not completely understood. To address this, we assessed the proteome of insulin resistant 3T3-L1 adipocytes and adipose tissue from mice and humans. We found lower expression of mevalonate/Coenzyme Q (CoQ) biosynthesis pathway proteins in insulin resistant samples. Analysis of subcellular CoQ content revealed selective depletion of CoQ from mitochondria in both insulin resistant adipose and muscle tissue. Given its role in electron transport, we investigated whether loss of CoQ caused insulin resistance via mitochondrial ROS. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered insulin resistance through increased mitochondrial ROS, while CoQ supplementation in either insulin resistant cell models or mice lowered ROS and restored insulin sensitivity. Our data place loss of mitochondrial CoQ upstream of mitochondrial ROS in the pathway to insulin resistance and suggest that interventions that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance