Mao Shuai, Yang Manqi, Liu Huimin, Wang Shun, Liu Man, Hu Shan, Liu Beilei, Ju Hao, Liu Zheyu, Huang Min, He Shuijing, Cheng Mian, Wu Gang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China.
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Biochim Biophys Acta Mol Basis Dis. 2025 Mar;1871(3):167650. doi: 10.1016/j.bbadis.2024.167650. Epub 2025 Jan 3.
Cardiac hypertrophy is characterized by the upregulation of fetal genes, increased protein synthesis, and enlargement of cardiac myocytes. The mechanistic target of rapamycin complex 1 (mTORC1), which responds to fluctuations in cellular nutrient and energy levels, plays a pivotal role in regulating protein synthesis and cellular growth. While attempts to inhibit mTORC1 activity, such as through the application of rapamycin and its analogs, have demonstrated limited efficacy, further investigation is warranted.
Here, we show that Serinc2 expression is downregulated in the transverse aortic constriction (TAC)-induced hypertrophic myocardium. Both in vivo and in vitro, the reduction of Serinc2 expression results in pathological hypertrophic growth, whereas Serinc2 overexpression exhibits a protective effect. RNA sequencing analysis following Serinc2 knockdown reveals a transcriptomic shift toward a pro-hypertrophic profile and suggests a significant interplay between Serinc2, amino acid, mTOR, and the lysosome, a hub for mTOR activation. Moreover, we show that Serinc2 localizes to lysosomes and hinders mTORC1 recruitment to the lysosomal membrane in response to amino acid stimulation, playing a critical role in regulating amino acid signaling pathway involved in the activation of p70S6K, S6, and 4EBP1 in Hela cells. And its deficiency exacerbates mTORC1 activity and mTORC1-dependent subsequent protein synthesis, which can be abrogated by rapamycin. In line with our in vitro findings, Serinc2 knockout mice subjected to TAC surgery exhibit elevated phosphorylation of p70S6K and 4EBP1, while inhibition of mTORC1 signaling through amino acid deprivation prevents this activation and impedes the progression to pathological cardiac remodeling.
We have illustrated that Serinc2 localizes to the lysosomal membrane and modulates amino acid /mTORC1 signaling in cardiomyocytes. Serinc2 therefore presents a potential therapeutic target for mitigating excessive protein synthesis and improving heart failure under hemodynamic stress.
心脏肥大的特征是胎儿基因上调、蛋白质合成增加和心肌细胞增大。雷帕霉素复合物1（mTORC1）是细胞营养和能量水平波动的响应分子，在调节蛋白质合成和细胞生长中起关键作用。虽然试图抑制mTORC1活性，如应用雷帕霉素及其类似物，已显示出有限的疗效，但仍需进一步研究。
在此，我们表明，在横断主动脉缩窄（TAC）诱导的肥厚心肌中，Serinc2表达下调。在体内和体外，Serinc2表达的降低都会导致病理性肥厚生长，而Serinc2过表达则具有保护作用。Serinc2敲低后的RNA测序分析显示转录组向促肥厚表型转变，并提示Serinc2、氨基酸、mTOR和溶酶体（mTOR激活的枢纽）之间存在显著相互作用。此外，我们表明Serinc2定位于溶酶体，并在氨基酸刺激下阻碍mTORC1募集到溶酶体膜，在调节Hela细胞中参与p70S6K、S6和4EBP1激活的氨基酸信号通路中起关键作用。其缺乏会加剧mTORC1活性和mTORC1依赖性后续蛋白质合成，而雷帕霉素可消除这种作用。与我们的体外研究结果一致，接受TAC手术的Serinc2基因敲除小鼠p70S6K和4EBP1的磷酸化水平升高，而通过氨基酸剥夺抑制mTORC1信号传导可阻止这种激活并阻碍病理性心脏重塑的进展。
我们已经阐明Serinc2定位于溶酶体膜并调节心肌细胞中的氨基酸/mTORC1信号传导。因此，Serinc2是减轻过度蛋白质合成和改善血流动力学应激下心力衰竭的潜在治疗靶点。
