TBC1D15/RAB7-regulated mitochondria-lysosome interaction confers cardioprotection against acute myocardial infarction-induced cardiac injury.

摘要: Rationale: Ischemic heart disease remains a primary threat to human health, while its precise etiopathogenesis is still unclear. TBC domain family member 15 (TBC1D15) RAB7 GTPase-activating protein participating in the regulation of mitochondrial dynamics. This study was designed explore role TBC1D15 acute myocardial infarction (MI)-induced cardiac injury and possible mechanism(s) involved. Methods: Mitochondria-lysosome interaction evaluated using transmission electron microscopy live cell time-lapse imaging. Mitophagy flux measured by fluorescence western blotting. Adult mice were transfected with adenoviral through intra-myocardium injection prior 3-day MI procedure. Cardiac morphology function at levels whole-heart, cardiomyocytes, intracellular organelles signaling transduction. Results: Our results revealed downregulated level TBC1D15, reduced systolic function, overt infarct area interstitial fibrosis, elevated cardiomyocyte apoptosis damage 3 days after MI. Overexpression restored alleviated although itself did not exert any effect absence Further examination that MI-induced accumulation damaged mitochondria associated blockade clearance because enlarged defective lysosomes subsequent interrupted mitophagy flux, which attenuated overexpression. Mechanistic studies showed provoked abnormal mitochondria-lysosome contacts, leading lysosomal enlargement subsequently disabled mitochondria. loosened contacts both Fis1 binding GAPase-activating as TBC1D15-dependent beneficial responses reversed interference either these two domains vitro vivo. Conclusions: findings indicated pivotal anomalies Fis1/RAB7 regulated lysosome-dependent activation, may provide new target clinical treatment