Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Republic of Korea.
Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea.
Nucleic Acids Res. 2022 Sep 9;50(16):9247-9259. doi: 10.1093/nar/gkac690.
Cells are constantly challenged by genotoxic stresses that can lead to genome instability. The integrity of the nuclear genome is preserved by the DNA damage response (DDR) and repair. Additionally, these stresses can induce mitochondria to transiently hyperfuse; however, it remains unclear whether canonical DDR is linked to these mitochondrial morphological changes. Here, we report that the abolition of mitochondrial fusion causes a substantial defect in the ATM-mediated DDR signaling. This deficiency is overcome by the restoration of mitochondria fusion. In cells with fragmented mitochondria, genotoxic stress-induced activation of JNK and its translocation to DNA lesion are lost. Importantly, the mitochondrial fusion machinery of MFN1/MFN2 associates with Sab (SH3BP5) and JNK, and these interactions are indispensable for the Sab-mediated activation of JNK and the ATM-mediated DDR signaling. Accordingly, the formation of BRCA1 and 53BP1 foci, as well as homology and end-joining repair are impaired in cells with fragmented mitochondria. Together, these data show that mitochondrial fusion-dependent JNK signaling is essential for the DDR, providing vital insight into the integration of nuclear and cytoplasmic stress signals.
细胞不断受到可能导致基因组不稳定的遗传毒性应激的挑战。核基因组的完整性通过 DNA 损伤反应 (DDR) 和修复来维持。此外，这些应激还可以诱导线粒体短暂地超融合；然而，规范的 DDR 是否与这些线粒体形态变化有关仍不清楚。在这里，我们报告说，线粒体融合的消除会导致 ATM 介导的 DDR 信号显著缺陷。通过恢复线粒体融合可以克服这种缺陷。在有碎片化线粒体的细胞中，遗传毒性应激诱导的 JNK 激活及其向 DNA 损伤部位的转移丢失。重要的是，MFN1/MFN2 的线粒体融合机制与 Sab (SH3BP5) 和 JNK 相关联，这些相互作用对于 Sab 介导的 JNK 激活和 ATM 介导的 DDR 信号至关重要。因此，在有碎片化线粒体的细胞中，BRCA1 和 53BP1 焦点的形成，以及同源和末端连接修复都受到损害。总之，这些数据表明，线粒体融合依赖性 JNK 信号对于 DDR 至关重要，为核质应激信号的整合提供了重要的见解。
