Snf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling

• Published in: Nature communications Vol. 8; no. 1; p. 14095
• Main Authors: Rines, Amy K., Chang, Hsiang-Chun, Wu, Rongxue, Sato, Tatsuya, Khechaduri, Arineh, Kouzu, Hidemichi, Shapiro, Jason, Shang, Meng, Burke, Michael A., Abdelwahid, Eltyeb, Jiang, Xinghang, Chen, Chunlei, Rawlings, Tenley A., Lopaschuk, Gary D., Schumacker, Paul T., Abel, E. Dale, Ardehali, Hossein
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.01.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/89; 14; 14/28; 14/34; 14/63; 38/111; 631/80/304; 631/80/86/2369; 64/60; 82; 82/29; 82/80; Animals; Apoptosis; Cardiomyocytes; Cardiovascular disease; Cell Cycle Proteins - metabolism; Cell death; Cell Line; Diabetes; Disease Models, Animal; Dogs; Down-Regulation; Endocrinology; Fatty acids; Female; Gene Knockdown Techniques; Genes; Glucose; Heart; HEK293 Cells; Humanities and Social Sciences; Humans; Ischemia; Isolated Heart Preparation; Kinases; Male; Medicine; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - metabolism; multidisciplinary; Myocardial Reperfusion Injury - pathology; Myocardium - cytology; Myocardium - metabolism; Oxidation; Peptides; PPAR alpha - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Repressor Proteins - metabolism; Science; Science (multidisciplinary); Uncoupling Protein 3 - metabolism; United States > US
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14095

Ischaemic heart disease limits oxygen and metabolic substrate availability to the heart, resulting in tissue death. Here, we demonstrate that the AMP-activated protein kinase (AMPK)-related protein Snf1-related kinase (SNRK) decreases cardiac metabolic substrate usage and mitochondrial uncoupling, and protects against ischaemia/reperfusion. Hearts from transgenic mice overexpressing SNRK have decreased glucose and palmitate metabolism and oxygen consumption, but maintained power and function. They also exhibit decreased uncoupling protein 3 (UCP3) and mitochondrial uncoupling. Conversely, Snrk knockout mouse hearts have increased glucose and palmitate oxidation and UCP3. SNRK knockdown in cardiac cells decreases mitochondrial efficiency, which is abolished with UCP3 knockdown. We show that Tribbles homologue 3 (Trib3) binds to SNRK, and downregulates UCP3 through PPARα. Finally, SNRK is increased in cardiomyopathy patients, and SNRK reduces infarct size after ischaemia/reperfusion. SNRK also decreases cardiac cell death in a UCP3-dependent manner. Our results suggest that SNRK improves cardiac mitochondrial efficiency and ischaemic protection. The Snf1-related kinase (SNRK) is widely expressed and yet its function is poorly understood. Here the authors show that SNRK regulates mitochondrial coupling via the Trib3-PPARα-UCP3 pathway and that cardiac overexpression of SNRK decreases metabolic substrate usage and oxygen consumption but maintains cardiac function and energy in mice.