Over the past few decades, the surge in the rates of obesity and type II diabetes in this nation has led to devastating health consequences. Stimulation of inducible mitochondrial thermogenesis, which wastes energy consumed as heat, is an attractive intervention strategy for obesity and related metabolic disorders. Uncoupling proteins (UCPs) are highly conserved thermogenic mediators that regulate inducible mitochondrial heat production in diverse tissues by controlling mitochondrial proton leak. In mammals, brown fat UCP1 is the established mediator of cold-induced thermogenesis. However, the low abundance of brown fat in a large percentage of adults challenges its thermoregulatory importance in these individuals and suggests that alternative thermogenic mechanisms exist. Skeletal muscle is also a key thermogenic organ in mammals, but whether UCPs are involved in muscle thermogenesis is unclear. We found that mice lacking the skeletal muscle-enriched UCP1 homolog UCP3 have sharply blunted (60- 100%) thermogenic responses to amphetamine-type stimulants, and the physiological fever inducers norepinephrine and lipopolysaccharide. In addition, mice specifically overexpressing UCP3 in muscle exhibit increased thermogenic responses. Fatty acids are essential activators of UCP1-3 induced proton leak, and therefore, thermogenesis. However, despite enormous efforts, the mechanistic basis for fatty acid activation of UCPs is unclear. Unsaturated, healthy fatty acids (e.g. oleate) are strong activators of UCPs relative to the more deleterious saturated analogs. Oleate and related fatty acids require auxiliary metabolic enzymes for full metabolism by beta oxidation. We found that UCP3 forms a novel, oleate- sensitive and functionally important interaction with 2,4, 3,5 dienoyl-CoA isomerase, a fatty acid metabolizing enzyme in the mitochondrial matrix whose substrates include many of the same fatty acids that bind and activate UCP3. Work in this grant will characterize the binding mechanisms and functional metabolic relevancy of this novel mitochondrial complex guided by three specific aims:
Aim 1 - To define the structural and bioenergetic mechanisms regulating the binding of dienoyl-CoA isomerase and UCP3.
Aim 2 - To establish the functional importance of dienoyl CoA isomerase for UCP3-induced mitochondrial uncoupling, and of UCP3 for the enzymatic activity of dienoyl CoA isomerase.
Aim 3 - To explore the physiological functions of dienoyl CoA isomerase as a key regulator of lipid induced thermogenesis and fat catabolism in muscle and other UCP-relevant thermoregulatory tissues.
Work in this proposal aims to determine the molecular mechanisms by which mitochondrial uncoupling protein 3 (UCP3) is activated in skeletal muscle. Specifically we will characterize a novel interaction between UCP3 and dienoyl CoA isomerase and its functional importance for skeletal muscle physiology. A greater mechanistic understanding of the regulation and functions of UCP3 as well as other thermogenic uncoupling proteins is greatly needed. This work will lay a foundation for the development of anti-obesity drugs that target UCP3-induced heat production in muscle.
|Nowinski, Sara M; Solmonson, Ashley; Rundhaug, Joyce E et al. (2015) Mitochondrial uncoupling links lipid catabolism to Akt inhibition and resistance to tumorigenesis. Nat Commun 6:8137|
|Razorenova, Olga V; Castellini, Laura; Colavitti, Renata et al. (2014) The apoptosis repressor with a CARD domain (ARC) gene is a direct hypoxia-inducible factor 1 target gene and promotes survival and proliferation of VHL-deficient renal cancer cells. Mol Cell Biol 34:739-51|
|Abe, Tomoki; Hirasaka, Katsuya; Kagawa, Sachiko et al. (2013) Cbl-b is a critical regulator of macrophage activation associated with obesity-induced insulin resistance in mice. Diabetes 62:1957-69|
|Kohno, Shohei; Yamashita, Yui; Abe, Tomoki et al. (2012) Unloading stress disturbs muscle regeneration through perturbed recruitment and function of macrophages. J Appl Physiol (1985) 112:1773-82|
|Lago, C U; Nowinski, S M; Rundhaug, J E et al. (2012) Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis. Oncogene 31:4725-31|
|Hirasaka, Katsuya; Lago, Cory U; Kenaston, M Alexander et al. (2011) Identification of a redox-modulatory interaction between uncoupling protein 3 and thioredoxin 2 in the mitochondrial intermembrane space. Antioxid Redox Signal 15:2645-61|
|Pfeiffer, Matthew; Kayzer, Ernst-Bernhard; Yang, Xianmei et al. (2011) Caenorhabditis elegans UCP4 protein controls complex II-mediated oxidative phosphorylation through succinate transport. J Biol Chem 286:37712-20|
|Hrometz, Sandra L; Thatcher, Karen E; Ebert, Jeremy A et al. (2011) Identification of a possible role for atrial natriuretic peptide in MDMA-induced hyperthermia. Toxicol Lett 206:234-7|