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

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 expression, which facilitated cancer cell growth and CRC development.