Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China.
Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, 100029, Beijing, China.
Cell Death Differ. 2023 Jul;30(7):1786-1798. doi: 10.1038/s41418-023-01179-0. Epub 2023 Jun 7.
The mitochondrial transmembrane (TMEM) protein family has several essential physiological functions. However, its roles in cardiomyocyte proliferation and cardiac regeneration remain unclear. Here, we detected that TMEM11 inhibits cardiomyocyte proliferation and cardiac regeneration in vitro. TMEM11 deletion enhanced cardiomyocyte proliferation and restored heart function after myocardial injury. In contrast, TMEM11-overexpression inhibited neonatal cardiomyocyte proliferation and regeneration in mouse hearts. TMEM11 directly interacted with METTL1 and enhanced mG methylation of Atf5 mRNA, thereby increasing ATF5 expression. A TMEM11-dependent increase in ATF5 promoted the transcription of Inca1, an inhibitor of cyclin-dependent kinase interacting with cyclin A1, which suppressed cardiomyocyte proliferation. Hence, our findings revealed that TMEM11-mediated mG methylation is involved in the regulation of cardiomyocyte proliferation, and targeting the TMEM11-METTL1-ATF5-INCA1 axis may serve as a novel therapeutic strategy for promoting cardiac repair and regeneration.
线粒体跨膜（TMEM）蛋白家族具有多种重要的生理功能。然而，其在心肌细胞增殖和心脏再生中的作用尚不清楚。本研究发现 TMEM11 抑制体外心肌细胞增殖和心脏再生。TMEM11 缺失可增强心肌细胞增殖并恢复心肌损伤后的心脏功能。相反，TMEM11 过表达抑制了小鼠心脏中的新生心肌细胞增殖和再生。TMEM11 可直接与 METTL1 相互作用，并增强 Atf5 mRNA 的 mG 甲基化，从而增加 ATF5 的表达。TMEM11 依赖性 ATF5 增加可促进与 cyclin A1 相互作用的细胞周期蛋白依赖性激酶抑制剂 Inca1 的转录，从而抑制心肌细胞增殖。因此，我们的研究结果表明，TMEM11 介导的 mG 甲基化参与调节心肌细胞增殖，靶向 TMEM11-METTL1-ATF5-INCA1 轴可能成为促进心脏修复和再生的新治疗策略。
