Targeting Cytoplasmic SAM by Expressing Slc25a26 Inhibits Protein Synthesis in Cardiac Hypertrophy via SAMTOR/mTOR signaling

Excess protein synthesis is the major pathological manifestation of cardiac hypertrophy; however, the underlying mechanism remains elusive. Here we found that a SAM transporter Slc25a26 translocated to mitochondria during cardiac hypertrophy. Silencing Slc25a26 aggravated phenylephrine-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes. Transcriptome analysis revealed a specific regulation of ribosome genes by Slc25a26. Puromycin incorporation assay showed a negative regulation of protein synthesis rate by Slc25a26. The translational regulation was independent of ribosome assembly, but abolished by mTOR inhibitor rapamycin. Administration of SAM, or silencing Samtor, reversed the inhibitory impact of Slc25a26 on protein synthesis. AAV9-mediated Slc25a26 overexpression in mouse heart increased the SAM level in mitochondria, but reduced that in nucleus and cytoplasm. Transaortic-constriction-induced hypertrophic pathologies, including pathological gene induction, cardiomyocyte enlargement, myocardial remodeling and heart dysfunction were significantly alleviated by Slc25a26 overexpression. Our data demonstrate a crucial role of subcellular SAM homeostasis in translational control during cardiac hypertrophy.蛋白质合成过度是心肌肥厚的主要病理表现，但其潜在机制仍未明确。本研究发现，S-腺苷甲硫氨酸（SAM）转运蛋白Slc25a26在心肌肥厚过程中转位至线粒体。在新生大鼠心室肌细胞中，沉默Slc25a26可加重苯肾上腺素诱导的心肌细胞肥大。转录组分析显示，Slc25a26可特异性调控核糖体基因的表达。嘌呤霉素掺入实验结果表明，Slc25a26对蛋白质合成速率具有负调控作用。该翻译调控过程不依赖于核糖体组装，但可被哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂雷帕霉素消除。外源性给予SAM或沉默Samtor基因，均可逆转Slc25a26对蛋白质合成的抑制作用。腺相关病毒9型（AAV9）介导的Slc25a26在小鼠心脏中的过表达，可升高线粒体中的SAM水平，同时降低细胞核与细胞质中的SAM水平。主动脉缩窄诱导的肥厚性病理改变，包括病理性基因诱导、心肌细胞增大、心肌重构及心功能障碍，均可通过Slc25a26过表达得到显著缓解。本研究数据证实，亚细胞水平的SAM稳态在心肌肥厚过程中的翻译调控中发挥关键作用。