AP39 pro-FUNDC1 mediated mitophagy regulates mitochondrial dynamics to improve HHCY-induced myocardial remodeling

Abstract Our previous studies have shown that hyper-homocysteinemia (HHCY) can induce myocardial fibrosis and remodeling, but the underlying mechanisms are not well understood. AP39, a newly synthesized mitochondrial-targeted H 2 S donor, has been shown to inhibit myocardial cell injury and endothelial cell aging, but its specific regulatory mechanisms are unclear. Therefore, in this study, we constructed an animal model of HHCY-induced myocardial remodeling in SD rats by drinking water containing L-methionine (10g/L), and observed that HHCY rats had decreased cardiac function, significant collagen fiber deposition in myocardial tissue, increased senescent cells in myocardial tissue, inhibited Mitophagy, and significantly imbalanced mitochondrial dynamics. AP39 intervention (100nM) could significantly reverse the above phenomena; similar changes were observed in vitro experiments. RNA-seq technology and quantitative PCR on H9c2 myocardial cells stimulated by HHCY showed that AP39 intervention could reverse the down-regulation of FUNDC1-mediated Mitophagy induced by HHCY, and RNA interference of FUNFC1 could eliminate the effect of AP39. In conclusion, the mitochondrial-targeted H 2 S donor AP39 may improve myocardial mitochondrial dynamics and stress-induced senescence by up-regulating FUNDC1-mediated Mitophagy, thereby improving HHCY-induced myocardial remodeling.