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.
Highlights
Ischaemic heart disease limits oxygen and metabolic substrate availability to the heart, resulting in tissue death
We demonstrated that TG Sucrose nonfermenting 1 (Snf1)-related kinase (SNRK) protein is expressed twofold relative to endogenous cardiac SNRK using a SNRK antibody (Fig. 1a)
The kinase-inactive SNRK-T173A mutant did not significantly decrease these parameters relative to the control (Supplementary Fig. 7a–d). These findings indicate that SNRK regulates metabolism and decreases oxygen consumption in the setting of hypoxia-reoxygenation, and suggest that SNRK may be protective during ischaemia/reperfusion
Summary
Ischaemic heart disease limits oxygen and metabolic substrate availability to the heart, resulting in tissue death. 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 exhibit decreased uncoupling protein 3 (UCP3) and mitochondrial uncoupling. Identification of novel proteins and pathways that modulate substrate metabolism to improve energy production from limited oxygen and substrate availability could potentially lead to new therapies aimed to increase metabolic efficiency and decrease tissue death during heart disease. The effects on substrate usage and cell death are dependent on UCP3, which is downregulated through suppression of PPARa by Trib[3], a novel binding partner of SNRK
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
