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

Abstract

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

Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation

“…Fis1 -deficient worms treated with mitochondrial toxins accumulate large autophagic structures ( Shen et al, 2014 ). Furthermore, Fis1 can regulate mitochondrion-lysosome contacts via the Tbc1d15/Rab7 pathway ( Wong et al, 2018 ; Yu et al, 2020 ), and can affect lysosomal function ( Joshi et al, 2019 ; Kim et al, 2016 ). Finally, Fis1 genetically interacts with the amyotrophic lateral sclerosis gene C9orf72 ( Chai et al, 2020 ), which is involved in membrane trafficking and autophagy ( Nassif et al, 2017 ).…”

Improvement Lipophagy by Restoring Rab7 Cycle: Protective Effects of Quercetin on Ethanol-Induced Liver Steatosis

“…This shows that the inactivation of Rab7 also can be regulated by phosphoinositides and provides a new direction for the study of Rab7 cyclical mechanism. In addition, since the circulation of Rab7 plays an important role in maintaining the normal function of the membrane contact sites (MCSs), including the formation of ERendosome MCSs mediated by GTP-Rab7 and the maintenance of normal mitochondria-lysosome MCSs dependent on its hydrolysis [75,76], which emphasizes the important role of Rab7 circulation in maintaining cellular homeostasis. Thus, the formation defect of the MCSs caused by Rab7 will be further explored in the ALD next step.…”

Advances in Cardiotoxicity Induced by Altered Mitochondrial Dynamics and Mitophagy

“…When excessive or continuous stress acts on the heart, the mitochondrial energy metabolism function and quality control system are seriously disturbed, which exceeds the self-regulation range of mitochondrial dynamics and mitophagy. On the one hand, it causes the energy metabolism of cardiac cells to become impaired, on the other hand, the mtDNA and ROS released by damaged mitochondria accumulate to reach a toxic concentration, which together lead to cardiotoxicity ( 25 , 66 , 115 – 117 ), the process of cardiotoxicity caused by different injury factors is shown in Figure 1 . Cardiotoxicity refers to cardiac damage caused by excessive accumulation of endogenous or exogenous substances to reach a toxic concentration ( 118 ).…”