부산대학교 도서관

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. [Display omitted] • Mitochondrial fission caused by mitochondrial dysfunction promotes DNA damage • Minority MOMP occurs on dysfunctional, fragmented mitochondria • Inter-mitochondrial heterogeneity in apoptotic priming underpins minority MOMP • BAX accumulates on dysfunctional, fragmented mitochondria, sensitizing them to MOMP Sub-lethal apoptotic stress can cause oncogenic DNA damage. Investigating its basis, Cao, Riley, and colleagues report that mitochondrial dysfunction promotes sub-lethal apoptotic stress. Mitochondrial dysfunction causes permeabilization of select mitochondria through mitochondrial fission and pro-apoptotic BAX mitochondrial accumulation. Therefore, mitochondrial function and genome stability are interconnected via sub-lethal apoptotic stress. [ABSTRACT FROM AUTHOR]