Parkin overexpression alleviates cardiac aging through facilitating K63-polyubiquitination of TBK1 to facilitate mitophagy.

Cumulative clinical and experimental evidence has revealed a cardinal role for mitochondrial integrity in cardiac aging. Parkin-mediated mitophagy is essential to ensure mitochondrial quality control in myocardium. This study was designed to examine the impact of Parkin overexpression on aging-induced myocardial anomalies and the underlying mechanisms with a focus on Parkin-regulated mitophagy. Cardiac function, myocardial apoptosis, mitochondrial ultrastructure and mitophagy were examined in young (3 mo) and old (24-26 mo) wild-type (WT) and Parkin transgenic mice. Our data revealed compromised myocardial function and mitochondrial morphology along with overtly apoptosis with advanced aging, the effects of which were attenuated by Parkin overexpression. Advanced aging dampened mitophagy as evidenced by decreased levels of Parkin, LC3II, phosphorylation of p62 and TBK1 in isolated mitochondria as well as reduced mitochondria autophagosomes, the effects of which were mitigated by restoration of mitophagy via Parkin overexpression. Using the low-dose doxorubicin (DOX) in vitro model of cell senescence, we noted that Parkin-offered beneficial effect against senescence was abolished by the TBK1 kinase inhibitor BX795. With TBK1 overexpression in cardiomyocytes, we uncovered the interaction of Parkin with TBK1 using a Co-immunoprecipitation (Co-IP) assay. The interaction of Parkin with TBK1 contributed to K63-linked polyubiquitination of TBK1. Our study also noted that DOX disturbed K63-linked polyubiquitination of TBK1 with downregulation of Parkin. Parkin overexpression promoted K63-linked polyubiquitination of TBK1 through Lys30 and Lys401 residues to foster TBK1 phosphorylation to facilitate efficient mitophagy. In summary, these findings suggested that Parkin effectively rescued cardiac aging through promoting K63-linked polyubiquitination of TBK1 to facilitate mitophagy.

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