Samm50 Promotes Hypertrophy by Regulating Pink1-Dependent Mitophagy Signaling in Neonatal Cardiomyocytes.

Ran Xu,Chunjie Yang,Zhiwen Ding,Yuanfeng Fu,Yunzeng Zou,Siang Wei,Le Kang

doi:10.3389/fcvm.2021.748156

Abstract

Pathological cardiac hypertrophy, the adaptive response of the myocardium to various pathological stimuli, is one of the primary predictors and predisposing factors of heart failure. However, its molecular mechanisms underlying pathogenesis remain poorly understood. Here, we studied the function of Samm50 in mitophagy during Ang II-induced cardiomyocyte hypertrophy via lentiviruses mediated knockdown and overexpression of Samm50 protein. We first found that Samm50 is a key positive regulator of cardiac hypertrophy, for western blot and real-time quantitative PCR detection revealed Samm50 was downregulated both in pressure-overload-induced hypertrophic hearts and Ang II-induced cardiomyocyte hypertrophy. Then, Samm50 overexpression exhibits enhanced induction of cardiac hypertrophy marker genes and cell enlargement in primary mouse cardiomyocytes by qPCR and immunofluorescence analysis, respectively. Meanwhile, Samm50 remarkably reduced Ang II-induced autophagy as indicated by decreased mitophagy protein levels and autophagic flux, whereas the opposite phenotype was observed in Samm50 knockdown cardiomyocytes. However, the protective role of Samm50 deficiency against cardiac hypertrophy was abolished by inhibiting mitophagy through Vps34 inhibitor or Pink1 knockdown. Moreover, we further demonstrated that Samm50 interacted with Pink1 and stimulated the accumulation of Parkin on mitochondria to initiate mitophagy by co-immunoprecipitation analysis and immunofluorescence. Thus, these results suggest that Samm50 regulates Pink1-Parkin-mediated mitophagy to promote cardiac hypertrophy, and targeting mitophagy may provide new insights into the treatment of cardiac hypertrophy.

Highlights

IntroductionA complex multifactorial syndrome, has become a worldwide problem reaching epidemic proportions
Heart failure, a complex multifactorial syndrome, has become a worldwide problem reaching epidemic proportions
To determine whether Samm50 expression is associated with cardiac hypertrophy, we performed the transverse aortic constriction (TAC) mice model (Supplementary Figures 1A–D) and found the mRNA, and protein levels of Samm50 were remarkably decreased in response to pressure overload (Figures 1A,B)

Summary

Introduction

A complex multifactorial syndrome, has become a worldwide problem reaching epidemic proportions. Cardiac hypertrophy is regarded as the leading cause of heart failure. The onset of cardiac hypertrophy is characterized by a fetal reprogramming of gene expression where adult genes are repressed and fetal genes are activated, resulting in an imbalance between protein synthesis and degradation [1,2,3]. The key inhibitor of the mTOR pathway rapamycin, which is a potent activator of autophagy, has been reported to prevent cardiac hypertrophy [10, 11]. A special autophagy, removes damaged or redundant mitochondria to maintain heart function in response to various stress and heart disease conditions. Pink is rapidly degraded when it is translocated into mitochondria. In any case, if Pink is accumulated in the outer membrane of mitochondria (OMM), it would phosphorylate Parkin leading to activating its ligase activity. A series of events eventually lead to the mitochondria being delivered to lysosomes [12,13,14,15,16,17,18]

Methods

Results

Conclusion