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

Author

Listed:
  • 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
    Present address: Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA)

  • Hossein Ardehali

    (Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University)

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.

Suggested Citation

  • 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 &, 2017. "Snf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14095
    DOI: 10.1038/ncomms14095
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