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

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.

Apelin‐13/APJ induces cardiomyocyte hypertrophy by activating the Pannexin‐1/P2X7 axis and FAM134B‐dependent reticulophagy

“…Excessive activation of autophagy can increase the predisposition to the pathogenesis of myocardial hypertrophy (Qi et al, 2020; C. Song et al, 2021). Xu et al have discovered that Pink1‐Parkin‐mediated mitophagy promotes the development of cardiac hypertrophy (Xu et al, 2021). Notably, autophagy dysfunction can occur in patients with hypertrophic cardiomyopathy and cardiac failure, whereas inhibition of abnormal autophagy could alleviate cardiac left ventricular hypertrophy (Jiang et al, 2021).…”

Identification of Differential Expression Genes between Volume and Pressure Overloaded Hearts Based on Bioinformatics Analysis

“…Transverse aortic constriction (TAC). Pressure overload was induced by TAC in 9 mice, according to methods we have previously described [ 41 ]. Mice were anesthetized by intraperitoneal injection of a mixture of ketamine (150 mg/kg) and xylazine (10 mg/kg), endotracheally intubated, and ventilated (type 7025, Harvard Apparatus, March-Hugstetten, Germany).…”

Therapeutic potentials of modulating autophagy in pathological cardiac hypertrophy.

“…Xu et al . found that SAMM50 sorting and assembly machinery component (Samm50), a key positive regulator of cardiac hypertrophy, promoted cardiac hypertrophy through regulating Pink1-Parkin-mediated mitophagy [42]. Shirakabe et al .…”