Abstract
Oxidative phosphorylation in mitochondria is responsible for 90% of ATP synthesis in most cells. This essential housekeeping function is mediated by nuclear and mitochondrial genes encoding subunits of complex I to V of the respiratory chain. Although complex IV is the best studied of these complexes, the exact function of the striated muscle-specific subunit COX6A2 is still poorly understood. In this study, we show that Cox6a2-deficient mice are protected against high-fat diet-induced obesity, insulin resistance and glucose intolerance. This phenotype results from elevated energy expenditure and a skeletal muscle fiber type switch towards more oxidative fibers. At the molecular level we observe increased formation of reactive oxygen species, constitutive activation of AMP-activated protein kinase, and enhanced expression of uncoupling proteins. Our data indicate that COX6A2 is a regulator of respiratory uncoupling in muscle and we demonstrate that a novel and direct link exists between muscle respiratory chain activity and diet-induced obesity/insulin resistance.
Highlights
The worldwide prevalence of type 2 diabetes and obesity has reached epidemic proportions as the result of the interaction of a Westernized lifestyle with genetic determinants that are prevalent in human populations
Since reduced complex IV activity is often associated with enhanced reactive oxygen species (ROS) production, and because intrinsic uncoupling of oxidative phosphorylation has been proposed to protect against the formation of ROS [28] we measured steady state ROS levels in the diaphragm and hindlimbs of Cox6a22/2 and WT mice utilizing dihydroethidium, which preferentially indicates superoxide [33]
Our results indicate that COX6A2 deficiency causes moderate loss of complex IV activity and increased ROS production in skeletal muscle
Summary
The worldwide prevalence of type 2 diabetes and obesity has reached epidemic proportions as the result of the interaction of a Westernized lifestyle with genetic determinants that are prevalent in human populations. Over the past few years, several studies have suggested that changes in mitochondrial function may be compensatory or even protective, rather than a cause of these diseases [16,17,18] It seems that mild mitochondrial dysfunction in muscle and liver in mice protects against obesity and diabetes [19], whereas mice with a progressive muscle-specific respiratory chain deficiency have reduced blood glucose levels and increased peripheral glucose uptake [20]. At high intramitochondrial ATP/ADP ratios (i.e. at rest), reconstituted bovine heart complex IV has decreased proton pumping capacity, referred to as intrinsic uncoupling or ‘‘slip’’ [25] This mechanism has been suggested to play a role in thermogenesis in heart and skeletal muscle at rest [26] as well as in the protection against the formation of mitochondrial ROS [27,28]. Our data demonstrate a previously unrecognized link between presence of the Cox6a2 gene in mice and the susceptibility to develop high-fat diet-induced obesity, insulin resistance and glucose intolerance
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