首页|N6-methyladenosine facilitates mitochondrial fusion of colorectal cancer cells via induction of GSH synthesis and stabilization of OPA1 mRNA
N6-methyladenosine facilitates mitochondrial fusion of colorectal cancer cells via induction of GSH synthesis and stabilization of OPA1 mRNA
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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.
m6Amitochondrial fusionglutathioneOPA1colorectal cancer
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China
Sun Yat-sen University Cancer Center
State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine,Guangzhou 510060,China
Department of Biomedical Sciences,City University of Hong Kong,Hong Kong 999077,China
Institute of Systems and Physical Biology,Shenzhen Bay Laboratory,Shenzhen 518067,China
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国家重点研发计划国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金Guangdong Basic and Applied Basic Research FoundationKey-Area Research and Development Program of Guangdong ProvinceOpen Program of Shenzhen Bay LaboratoryGuangdong Provincial Key Laboratory of Construction FoundationShenzhen Bay Scholars Program
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