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Abstract：
Mitochondria undergo fission and fusion that are critical for cell survival and cancer development, while the regulatory factors for mitochondrial dynamics remain elusive. Herein we found that RNA m6A accelerated mitochondria fusion of colorectal cancer (CRC) cells. Metabolomics analysis and function studies indicated that m6A triggered the generation of glutathione (GSH) via the upregulation of RRM2B-a p53-inducible ribonucleotide reductase subunit with anti-reactive oxygen species potential. This in turn resulted in the mitochondria fusion of CRC cells. Mechanistically, m6A methylation of A1240 at 3\'UTR of RRM2B increased its mRNA stability via binding with IGF2BP2. Similarly, m6A methylation of A2212 at the coding sequence (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 the m6A/mitochondrial dynamics in tumor growth and CRC progression. Collectively, m6A promoted mitochondria fusion via induction of GSH synthesis and OPA1 expression, which facilitated cancer cell growth and CRC development.
摘要：
线粒体经历分裂和融合，这对细胞存活和癌症发展至关重要，而线粒体动力学的调节因子仍然难以捉摸。在本文中，我们发现RNAm6A加速了结直肠癌（CRC）细胞的线粒体融合。代谢组学分析和功能研究表明，m6A通过上调RRM2B-一种具有抗活性氧潜能的p53诱导型核糖核苷酸还原酶亚基来触发谷胱甘肽（GSH）的产生。这又导致CRC细胞的线粒体融合。机械上,在RRM2B的3'UTR处A1240的m6A甲基化通过与IGF2BP2结合增加其mRNA稳定性。同样，OPA1-线粒体内膜融合的必需GTP酶蛋白的编码序列（CDS）上A2212的m6A甲基化也增加了mRNA的稳定性并触发了线粒体融合。通过甲基转移酶抑制剂STM2457或dm6ACRISPR系统靶向m6A显著抑制线粒体融合。体内和临床数据证实了m6A/线粒体动力学在肿瘤生长和CRC进展中的积极作用。总的来说，m6A通过诱导GSH合成和OPA1表达促进线粒体融合，这促进了癌细胞的生长和CRC的发展。
