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

查看全文 作　　者：Jiawang [1]Zhou;Haisheng [1]Zhang;Ke [1]Zhong;Lijun [1]Tao;Yu [1]Lin;Guoyou [1]Xie;Yonghuang [1]Tan;You [1]Wu;Yunqing [1]Lu;Zhuojia [2]Chen;Jiexin [1]Li;Xin [3]Deng;Qin [4]Peng;Zigang [4]Li;Hongsheng [1]Wang 高影响力作者 机构地区：[1]Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China;[2]Sun Yat-sen University Cancer Center/State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine,Guangzhou 510060,China;[3]Department of Biomedical Sciences,City University of Hong Kong,Hong Kong 999077,China;[4]Institute of Systems and Physical Biology,Shenzhen Bay Laboratory,Shenzhen 518067,China高影响力机构 出　　处：《National Science Review》索引2024年第11卷第3期,共20页高影响力期刊 基　　金：supported by the National Key Research and Development Program of China(2022YFC2601800);the National Natural Science Foundation of China(32161143017,82173833,82372743,82173126,82373893 and 82341053);the Guangdong Basic and Applied Basic Research Foundation(2023B1515040006);the Key-Area Research and Development Program of Guangdong Province(2023B1111020007);the Open Program of Shenzhen Bay Laboratory(SZBL202009051006);the Guangdong Provincial Key Laboratory of Construction Foundation(2023B1212060022);the Shenzhen Bay Scholars Program. 摘　　要：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 m^(6)A accelerated mitochondria fusion of colorectal cancer(CRC)cells.Metabolomics analysis and function studies indicated that m^(6)A 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,m^(6)A methylation of A1240 at 3'UTR of RRM2B increased its mRNA stability via binding with IGF2BP2.Similarly,m^(6)A 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 m^(6)A through the methyltransferase inhibitor STM2457 or the dm^(6)ACRISPR system significantly suppressed mitochondria fusion.In vivo and clinical data confirmed the positive roles of the m^(6)A/mitochondrial dynamics in tumor growth and CRC progression.Collectively,m^(6)A promoted mitochondria fusion via induction of GSH synthesis and OPA1 expression,which facilitated cancer cell growth and CRC development. 关 键 词：m^(6)A mitochondrial fusion GLUTATHIONE OPA1 colorectal cancer
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