Identification of a fatty acid-sensitive interaction between mitochondrial uncoupling protein 3 and enoyl-CoA hydratase 1 in skeletal muscle

Summary Skeletal muscle mitochondrial fatty acid (FA) overload in response to chronic overnutrition is a prominent pathophysiological mechanism in obesity-induced metabolic disease. Increased disposal of FAs is therefore an attractive strategy for intervening in obesity and related disorders. Skeletal muscle uncoupling protein 3 (UCP3) activity is associated with increased FA oxidation and antagonizes weight gain in mice on obesogenic diets, but the mechanisms involved are not clear. Here, we show that UCP3 forms a direct, FA-stimulated, mitochondrial matrix-localized complex with the auxiliary unsaturated FA-metabolizing enzyme, Δ 3,5- Δ 2,4 dienoyl-CoA-isomerase (ECH1). Expression studies in C2C12 myoblasts that functionally augments state 4 (uncoupled) respiration and FA oxidation in skeletal myocytes. Mechanistic studies indicate that ECH1:UCP3 complex formation is likely stimulated by FA import into the mitochondria to enhance uncoupled respiration and unsaturated FA oxidation in mouse skeletal myocytes. In order to characterize the contribution of ECH1-dependent FA metabolism in NST, we generated an ECH1 knockout mouse and found that these mice were severely cold intolerant, despite an up-regulation of UCP3 expression in SKM. These findings illuminate a novel mechanism that links unsaturated FA metabolism with mitochondrial uncoupling and non-shivering thermogenesis in SKM.