Accumulating evidence suggests that autophagy dysfunction plays a critical role involved in myocardial ischemia/reperfusion (I/R) injury. However, the underling mechanism of malfunctional autophagy in the cardiomyocytes subjected to I/R has not been well defined. Here, we used an in vitro and an in vivo I/R model to monitor the autophagic flux in the cardiomyocytes, by exposing neonatal rat ventricular myocytes (NRVM) to hypoxia/reoxygenation (H/R) and by subjecting mice to I/R, respectively. We observed that autophagic flux in cardiomyocytes subjected to I/R was blocked in both the in vitro and the in vivo models, and down-regulating a lysosomal cationic channel, TRPML1, markedly liberated the blocked myocardial autophagic flux in I/R, demonstrating that TRPML1 contributes to the blocked autophagic flux in cardiomyocytes subjected to I/R. Mechanistically, a large quantity of reactive oxygen species (ROS) generated from the reperfusion process stimulated TRPML1 channels, activation of which in turn inhibited autophagic flux in cardiomyocytes presumably by disturbing the fusion between autophagosomes and lysosomes. As a result, the inhibited myocardial autophagic flux induced by TRPML1 damaged mitochondria turnover and resulted in mass accumulation of damaged mitochondria and detrimental ROS further release, which directly led to cardiomyocytes death. More importantly, pharmacological and genetic inhibition of TRPML1 channels greatly reduces infarct size and rescues heart function in mice subjected to I/R in vivo by restoring impaired myocardial autophagy. In summary, our study demonstrates that secondary to ROS elevation, activation of TRPML1 results in autophagy inhibition in cardiomyocytes subjected to I/R, which directly leads to cardiomyocytes death by disrupting mitochondria turnover. Therefore, targeting TRPML1 represents a novel therapeutic strategy to protect against myocardial I/R injury.
 

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