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; Xinghang Jiang; Chunlei Chen; Tenley A. Rawlings; Gary D. Lopaschuk; Paul T. Schumacker; E. Dale Abel; Hossein Ardehali

doi:10.1038/ncomms14095

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, Xinghang Jiang, Chunlei Chen, Tenley A. Rawlings, Gary D. Lopaschuk, Paul T. Schumacker, E. Dale Abel, Hossein Ardehali^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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.

Original language	English (US)
Article number	14095
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14095
State	Published - Jan 24 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Rines, A. K., Chang, H. C., Wu, R., Sato, T., Khechaduri, A., Kouzu, H., Shapiro, J., Shang, M., Burke, M. A., Jiang, X., Chen, C., Rawlings, T. A., Lopaschuk, G. D., Schumacker, P. T., Abel, E. D., & Ardehali, H. (2017). Snf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling. Nature communications, 8, Article 14095. https://doi.org/10.1038/ncomms14095

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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.",

author = "Rines, {Amy K.} and Chang, {Hsiang Chun} and Rongxue Wu and Tatsuya Sato and Arineh Khechaduri and Hidemichi Kouzu and Jason Shapiro and Meng Shang and Burke, {Michael A.} and Xinghang Jiang and Chunlei Chen and Rawlings, {Tenley A.} and Lopaschuk, {Gary D.} and Schumacker, {Paul T.} and Abel, {E. Dale} and Hossein Ardehali",

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AU - Rines, Amy K.

AU - Chang, Hsiang Chun

AU - Wu, Rongxue

AU - Sato, Tatsuya

AU - Khechaduri, Arineh

AU - Kouzu, Hidemichi

AU - Shapiro, Jason

AU - Shang, Meng

AU - Burke, Michael A.

AU - Jiang, Xinghang

AU - Chen, Chunlei

AU - Rawlings, Tenley A.

AU - Lopaschuk, Gary D.

AU - Schumacker, Paul T.

AU - Abel, E. Dale

AU - Ardehali, Hossein

PY - 2017/1/24

Y1 - 2017/1/24

N2 - 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.

AB - 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.

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

Abstract

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