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.
线粒体经历的分裂与融合对细胞存活和癌症发展至关重要，但线粒体动力学的调控因子尚不明确。本研究发现，RNA m6A修饰可加速结直肠癌细胞的线粒体融合。代谢组学分析与功能研究表明，m6A通过上调RRM2B（一种具有抗氧化应激潜力的p53诱导型核糖核苷酸还原酶亚基）来触发谷胱甘肽的生成，进而促进结直肠癌细胞的线粒体融合。机制上，RRM2B基因3′UTR区A1240位的m6A甲基化通过与IGF2BP2结合增强了其mRNA稳定性。同样，线粒体内膜融合关键GTP酶蛋白OPA1编码序列A2212位的m6A甲基化也提高了mRNA稳定性并引发线粒体融合。使用甲基转移酶抑制剂STM2457或dm6ACRISPR系统靶向m6A修饰可显著抑制线粒体融合。体内实验与临床数据均证实m6A/线粒体动力学对肿瘤生长和结直肠癌进展具有正向调控作用。综上，m6A通过诱导谷胱甘肽合成和OPA1表达促进线粒体融合，从而加速癌细胞生长和结直肠癌发展。
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