中山大学王红胜团队发现，N6-甲基腺苷通过诱导GSH合成和稳定OPA1 mRNA促进结直肠癌细胞线粒体融合。2024年1月29日，《国家科学评论》杂志在线发表了这一最新研究成果。

研究人员发现RNA m6A可加速结直肠癌细胞线粒体的融合。代谢组学分析和功能研究表明，m⁶A可通过上调RRM2B（一种p53诱导的核糖核苷酸还原酶亚基，具有抗ROS的潜能）引发谷胱甘肽的生成。这反过来又导致了CRC细胞线粒体的融合。从机理上讲，RRM2B 3'UTR的A1240 m⁶A甲基化通过与IGF2BP2结合增加了其mRNA的稳定性。同样，m⁶A甲基化线粒体内膜融合所必需的GTPase蛋白OPA1 CDS上的A2212，也能增加mRNA的稳定性并引发线粒体融合。

通过甲基转移酶抑制剂STM2457或dm⁶ACRISPR系统靶向m⁶A能显著抑制线粒体融合。体内和临床数据证实了，m⁶A/线粒体活力在肿瘤生长和CRC进展中的积极作用。总之，m⁶A通过诱导GSH合成和OPA1表达促进线粒体融合，从而促进癌细胞生长和CRC的发展。

据了解，线粒体发生分裂和融合对细胞存活和癌症发展至关重要，而线粒体动态的调控因子仍然难以捉摸。

附：英文原文

Title: N6-methyladenosine facilitates mitochondrial fusion of colorectal cancer cells via induction of GSH synthesis and stabilization of OPA1 mRNA

Author: Zhou, Jiawang, Zhang, Haisheng, Zhong, Ke, Tao, Lijun, Lin, Yu, Xie, Guoyou, Tan, Yonghuang, Wu, You, Lu, Yunqing, Chen, Zhuojia, Li, Jiexin, Deng, Xin, Peng, Qin, Li, Zigang, Wang, Hongsheng

Issue&Volume: 2024-01-29

Abstract: Mitochondria undergo fission and fusion is critical for cell survival and cancer development, while the regulatory factors for mitochondrial dynamic remain elusive. Herein we found that RNA m6A accelerated mitochondria fusion of colorectal cancer cells. Metabolomics analysis and function studies indicated that m6A triggered the generation of glutathione via the upregulation of RRM2B, a p53-inducible ribonucleotide reductase subunit with anti-ROS potential. This in turn resulted in the mitochondria fusion of CRC cells. Mechanistically, m6A methylation of A1240 at 3’UTR of RRM2B which increased its mRNA stability via binding with IGF2BP2. Similarly, m6A methylation of A2212 at the CDS of OPA1, an essential GTPase protein for mitochondrial inner membrane fusion, also increased mRNA stability and triggered mitochondria fusion. Targeting m6A through the methyltransferase inhibitor STM2457 or the dm6ACRISPR system significantly suppressed mitochondria fusion. In vivo and clinical data confirmed the positive roles of m6A/mitochondrial dynamic in tumor growth and CRC progression. Collectively, m6A promoted mitochondria fusion via induction of GSH synthesis and OPA1 expres

DOI: 10.1093/nsr/nwae039

Source: https://dx.doi.org/10.1093/nsr/nwae039