The dynamic regulation of mitochondria through fission and fusion is essential for maintaining cellular homeostasis. In this study, we discovered a role of coactivator-associated arginine methyltransferase 1 (CARM1) in mitochondrial dynamics. CARM1 methylates specific residues (R403 and R634) on dynamin-related protein 1 (DRP1). Methylated DRP1 interacts with mitochondrial fission factor (Mff) and forms self-assembly on the outer mitochondrial membrane, thereby triggering fission, reducing oxygen consumption, and increasing reactive oxygen species (ROS) production. This sets in motion a feedback loop that facilitates the translocation of CARM1 from the nucleus to the cytoplasm, enhancing DRP1 methylation and ROS production through mitochondrial fragmentation. Consequently, ROS reinforces the CARM1-DRP1-ROS axis, resulting in cellular senescence. Depletion of CARM1 or DRP1 impedes cellular senescence by reducing ROS accumulation. The uncovering of the above-described mechanism fills a missing piece in the vicious cycle of ROS-induced senescence and contributes to a better understanding of the aging process.

中文翻译：

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ROS 介导的 CARM1 细胞质定位通过 DRP1 甲基化诱导线粒体裂变


通过裂变和融合对线粒体进行动态调节对于维持细胞稳态至关重要。在这项研究中，我们发现了共激活剂相关精氨酸甲基转移酶 1 (CARM1) 在线粒体动力学中的作用。 CARM1 甲基化动力相关蛋白 1 (DRP1) 上的特定残基（R403 和 R634）。甲基化 DRP1 与线粒体裂变因子 (Mff) 相互作用，并在线粒体外膜上形成自组装，从而引发裂变，减少耗氧量并增加活性氧 (ROS) 的产生。这启动了一个反馈环路，促进 CARM1 从细胞核易位到细胞质，通过线粒体碎片增强 DRP1 甲基化和 ROS 产生。因此，ROS 增强了 CARM1-DRP1-ROS 轴，导致细胞衰老。 CARM1 或 DRP1 的耗竭通过减少 ROS 积累来阻止细胞衰老。上述机制的发现填补了ROS诱导衰老恶性循环中的缺失部分，有助于更好地理解衰老过程。