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

2019 ◽  
Author(s):  
Christine K. Dao ◽  
Alexander Kenaston ◽  
Katsuya Hirasaka ◽  
Shohei Kohno ◽  
Christopher Riley ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Uncoupling Protein ◽  
Pathophysiological Mechanism ◽  
Mitochondrial Uncoupling ◽  
Skeletal Myocytes ◽  
Mitochondrial Uncoupling Protein ◽  
Uncoupling Protein 3 ◽  
Mitochondrial Fatty Acid ◽  
Metabolizing Enzyme

SummarySkeletal 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, Δ3,5-Δ2,4dienoyl-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.

The energetic implications of uncoupling protein-3 in skeletal muscle

2007 ◽  
Vol 32 (5) ◽  
pp. 884-894 ◽  
Author(s):  
Sheila R. Costford ◽  
Erin L. Seifert ◽  
Véronic Bézaire ◽  
Martin F. Gerrits ◽  
Lisa Bevilacqua ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Molecular Mechanisms ◽  
Uncoupling Protein ◽  
Proton Leak ◽  
Ros Production ◽  
Uncoupling Protein 3 ◽  
Brown Adipose ◽  
Mitochondrial Fatty Acid

Despite almost a decade of research since the identification of uncoupling protein-3 (UCP3), the molecular mechanisms and physiological functions of this mitochondrial anion carrier protein are not well understood. Because of its highly selective expression in skeletal muscle and the existence of mitochondrial proton leak in this tissue, early reports proposed that UCP3 caused a basal proton leak and increased thermogenesis. However, gene expression data and results from knockout and overexpression studies indicated that UCP3 does not cause basal proton leak or physiological thermogenesis. UCP3 expression is associated with increases in circulating fatty acids and in fatty acid oxidation (FAO) in muscle. Fatty acids are also well recognized as activators of the prototypic UCP1 in brown adipose tissue. This has led to hypotheses implicating UCP3 in mitochondrial fatty acid translocation. The corresponding hypothesized physiological roles include facilitated FAO and protection from the lipotoxic effects of fatty acids. Recent in vitro studies of physiological increases in UCP3 in muscle cells demonstrate increased FAO, and decreased reactive oxygen species (ROS) production. Detailed mechanistic studies indicate that ROS or lipid by-products of ROS can activate a UCP3-mediated proton leak, which in turn acts in a negative feedback loop to mitigate ROS production. Altogether, UCP3 appears to play roles in muscle FAO and mitigated ROS production. Future studies will need to elucidate the molecular mechanisms underlying increased FAO, as well as the physiological relevance of ROS-activated proton leak.

Sign in / Sign up

Export Citation Format

Share Document