title: Snf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling.
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.
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Rines
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Hsiang-Chun
authors.initials: HC
authors.lastname: Chang
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Rongxue
authors.initials: R
authors.lastname: Wu
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sato
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Arineh
authors.initials: A
authors.lastname: Khechaduri
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Hidemichi
authors.initials: H
authors.lastname: Kouzu
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Shapiro
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Shang
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Burke
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Eltyeb
authors.initials: E
authors.lastname: Abdelwahid
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Xinghang
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Chen
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, School of Medicine, Salt Lake City, Utah 84132, USA.
authors.forename: Tenley A
authors.initials: TA
authors.lastname: Rawlings
authors.affiliation: Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada T6G 2B7.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Schumacker
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, School of Medicine, Salt Lake City, Utah 84132, USA.
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Hossein
authors.initials: H
authors.lastname: Ardehali
mesh_terms: D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D004285:Dogs; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D000067268:Isolated Heart Preparation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000473:pathology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D000071247:Uncoupling Protein 3 / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D047493:PPAR alpha; D012097:Repressor Proteins; C474830:TRB3 protein, mouse; C474831:TRIB3 protein, human; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; C490993:Snrk protein, mouse; C490994:SNRK protein, human; D017346:Protein Serine-Threonine Kinases