Heat stress promotes myocardial injury and ventricular arrhythmia through DRP1-mediated mitochondrial dysfunction.
With global warming, extreme summer heat has led to a higher morbidity and mortality of heat stroke (HS). Although heat stress has been linked to arrhythmias and cardiomyocyte injury, the specific molecular mechanisms and effective intervention strategies remain to be clarified.
We retrospectively collected clinical data from HS patients. A rat HS model was established, and the underlying mechanisms were investigated using biochemical and electrophysiological approaches, combined with proteomics and metabolomics analyses of myocardial tissues and cells. In vivo and in vitro intervention experiments were performed using the mitochondrial reactive oxygen species (ROS) scavenger MitoTEMPO and calcineurin inhibitor (FK506).
Heat stress caused severe myocardial injury and electrocardiographic abnormalities in HS patients. HS rats exhibited increased susceptibility to ventricular arrhythmias (VAs), manifested by prolonged action potential duration (APD), increased Ca2+ transient duration (CaTD) and Ca2+ alternans ratio, and slowed conduction velocity (CV), which were linked to disrupted Ca2+ handling. Proteomics and metabolomics revealed that mitochondrial dysfunction was closely associated with heat stress-induced myocardial injury. Mechanistically, HS triggers intracellular Ca2+ overload, activating calcineurin. Calcineurin dephosphorylates DRP1 at Ser637 site and promotes its mitochondrial translocation, leading to DRP1-mediated mitochondrial fission and dysfunction, excessive mitochondrial ROS generation, and cardiomyocyte apoptosis. In addition, MitoTEMPO and FK506 treatment partially reversed HS-induced myocardial injury and VAs susceptibility by scavenging mitochondrial ROS and restoring mitochondrial function.
Heat stress triggers mitochondrial dysfunction through a Ca2+/ calcineurin/ p-DRP1(Ser637) axis, resulting in myocardial injury and VAs. The mitochondria-targeted antioxidant MitoTEMPO and FK506 partially alleviate these adverse effects by scavenging mitochondrial ROS and restoring mitochondrial function.
We retrospectively collected clinical data from HS patients. A rat HS model was established, and the underlying mechanisms were investigated using biochemical and electrophysiological approaches, combined with proteomics and metabolomics analyses of myocardial tissues and cells. In vivo and in vitro intervention experiments were performed using the mitochondrial reactive oxygen species (ROS) scavenger MitoTEMPO and calcineurin inhibitor (FK506).
Heat stress caused severe myocardial injury and electrocardiographic abnormalities in HS patients. HS rats exhibited increased susceptibility to ventricular arrhythmias (VAs), manifested by prolonged action potential duration (APD), increased Ca2+ transient duration (CaTD) and Ca2+ alternans ratio, and slowed conduction velocity (CV), which were linked to disrupted Ca2+ handling. Proteomics and metabolomics revealed that mitochondrial dysfunction was closely associated with heat stress-induced myocardial injury. Mechanistically, HS triggers intracellular Ca2+ overload, activating calcineurin. Calcineurin dephosphorylates DRP1 at Ser637 site and promotes its mitochondrial translocation, leading to DRP1-mediated mitochondrial fission and dysfunction, excessive mitochondrial ROS generation, and cardiomyocyte apoptosis. In addition, MitoTEMPO and FK506 treatment partially reversed HS-induced myocardial injury and VAs susceptibility by scavenging mitochondrial ROS and restoring mitochondrial function.
Heat stress triggers mitochondrial dysfunction through a Ca2+/ calcineurin/ p-DRP1(Ser637) axis, resulting in myocardial injury and VAs. The mitochondria-targeted antioxidant MitoTEMPO and FK506 partially alleviate these adverse effects by scavenging mitochondrial ROS and restoring mitochondrial function.
Authors
Xiang Xiang, Han Han, Cao Cao, Shao Shao, Yang Yang, Sun Sun, Zhang Zhang, Huang Huang, Li Li, Sun Sun, Li Li, Liu Liu, Huang Huang, Lei Lei, Li Li, Li Li, Zhang Zhang, Tang Tang
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