Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage

被引:62
作者
Cao, Kai [1 ,2 ,3 ]
Riley, Joel S. [1 ,2 ,4 ]
Heilig, Rosalie [1 ,2 ]
Montes-Gomez, Alfredo E. [1 ,2 ]
Vringer, Esmee [1 ,2 ]
Berthenet, Kevin [5 ,6 ]
Cloix, Catherine [1 ,2 ]
Elmasry, Yassmin [1 ,2 ]
Spiller, David G. [7 ]
Ichim, Gabriel [5 ,6 ]
Campbell, Kirsteen J. [1 ,2 ]
Gilmore, Andrew P. [8 ]
Tait, Stephen W. G. [1 ,2 ]
机构
[1] Canc Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland
[2] Univ Glasgow, Coll Med Vet & Life Sci, Inst Canc Sci, Glasgow G61 1QH, Lanark, Scotland
[3] Beijing Univ Technol, Fac Environm & Life Sci, Dept Chem & Biol, Beijing 100124, Peoples R China
[4] Med Univ Innsbruck, Inst Dev Immunol, Bioctr, Innsbruck, Austria
[5] CNRS, 5286, INSERM, 1052,Canc Res Ctr Lyon CRCL, Lyon, France
[6] Univ Lyon, Canc Cell Death Lab, Part LabEx DEVweCAN, Lyon, France
[7] Univ Manchester, Fac Biol Med & Hlth, Syst Microscopy, Manchester M13 9PT, Lancs, England
[8] Univ Manchester, Manchester Acad, Sci Ctr, Fac Biol Med & Hlth,Wellcome Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England
基金
瑞士国家科学基金会; 英国惠康基金;
关键词
APOPTOSIS; FISSION; CANCER; BAX; FUMARATE; RELEASE; PATHWAY; FUSION; DRP1;
D O I
10.1016/j.devcel.2022.03.019
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage and genome instability. The ability of mitochondrial dynamics to regulate oncogenic DNA damage centers upon the control of minority mitochondrial outer membrane permeabilization (MOMP), a process that enables non-lethal caspase activation leading to DNA damage. Mitochondrial fusion suppresses minority MOMP and its associated DNA damage by enabling homogeneous mitochondrial expression of anti-apoptotic BCL-2 proteins. Finally, we find that mitochondrial dysfunction inhibits pro-apoptotic BAX retrotranslocation, causing BAX mitochondrial localization and thereby promoting minority MOMP. Unexpectedly, these data reveal oncogenic effects of mitochondrial dysfunction that are mediated via mitochondrial dynamics and caspase-dependent DNA damage.
引用
收藏
页码:1211 / +
页数:22
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