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

Amy K. Rines, Hsiang-Chun Chang, Rongxue Wu, Tatsuya Sato, Arineh Khechaduri, Hidemichi Kouzu, Jason Shapiro, Meng Shang, Michael A. Burke, Eltyeb Abdelwahid, Xinghang Jiang, Chunlei Chen, Tenley A. Rawlings, Gary D. Lopaschuk, Paul T. Schumacker, E. Dale Abel and Hossein Ardehali ()
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Amy K. Rines: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University
Hsiang-Chun Chang: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University
Rongxue Wu: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University
Tatsuya Sato: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University
Arineh Khechaduri: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University
Hidemichi Kouzu: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University
Jason Shapiro: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University
Meng Shang: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University
Michael A. Burke: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University
Eltyeb Abdelwahid: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University
Xinghang Jiang: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University
Chunlei Chen: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University
Tenley A. Rawlings: Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, School of Medicine
Gary D. Lopaschuk: Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta
Paul T. Schumacker: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University
E. Dale Abel: Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, School of Medicine
Hossein Ardehali: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms14095

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