Abstract 12864: Trim69 Alleviates Heart Aging and Mitochondrial Dysfunction by Restoring Mitophagy Through P53-Related Pathway

Abstract

Introduction: Cardiac aging is defined as the heart structural and functional abnormality, manifesting as the aging-associated functional decline and the aging phenotypes. Trim69 is an E3 ubiquitin-protein ligase representing the potential to alleviate cardiac aging through poorly defined mechanisms. Hypothesis: Whether Trim69 signaling improves cardiac aging, and if so to further explore the underlying mechanism. Methods: The SD rats were subjected to subcutaneous injection of low-dose D-gal in the nape for 8 weeks to induce senility. The recombinant lentivirus was transmitted by myocardial multipoint injection to overexpress Trim69 in vivo. The assessment of cardiac function and aging-associated phenotypes were enforced through an ECG, β-gal staining, Masson staining, WGA staining, and western blot. Cardiac mitochondrial structure and mitophagy were observed through electron microscopy in vivo , which were detected by a mitophagy detection kit and JC-1 staining in vitro . H9C2 cardiomyocyte line derived from rats' embryonic stem cells was used to explore the protective effects and mechanism of Trim69 against D-gal-induced cardiac aging and mitochondrial dysfunction. Results: After 8 weeks of D-gal induction, the heart function of rats significantly declined, with marked manifestations of senility including positive for β-gal staining, increased oxidative stress, noticeable myocardial hypertrophy, and progression of myocardial fibrosis. Trim69 overexpression alleviated D-gal-induced cardiac dysfunction and mitochondrial damage, accompanied by mitophagy recovery. Mechanistically, Trim69 directly binds with P53 and promotes its ubiquitination and degradation, reversing the D-gal-induced mitophagy suppression via Parkin/Pink1 axis. Conclusions: Overexpression of Trim69 could promote ubiquitin degradation of P53, which further inhibits the accumulation of P53, therefore alleviate the cardiac aging and mitochondrial dysfunction.