Moretton Amandine, Morel Frédéric, Macao Bertil, Lachaume Philippe, Ishak Layal, Lefebvre Mathilde, Garreau-Balandier Isabelle, Vernet Patrick, Falkenberg Maria, Farge Géraldine
Université Clermont Auvergne, CNRS/IN2P3, Laboratoire de Physique de Clermont, BP 10448, F-63000 Clermont-Ferrand, France.
Institute of Biomedicine, University of Gothenburg, P.O. Box 440, SE-405 30, Gothenburg, Sweden.
PLoS One. 2017 Apr 28;12(4):e0176795. doi: 10.1371/journal.pone.0176795. eCollection 2017.
Mitochondrial DNA (mtDNA) can undergo double-strand breaks (DSBs), caused by defective replication, or by various endogenous or exogenous sources, such as reactive oxygen species, chemotherapeutic agents or ionizing radiations. MtDNA encodes for proteins involved in ATP production, and maintenance of genome integrity following DSBs is thus of crucial importance. However, the mechanisms involved in mtDNA maintenance after DSBs remain unknown. In this study, we investigated the consequences of the production of mtDNA DSBs using a human inducible cell system expressing the restriction enzyme PstI targeted to mitochondria. Using this system, we could not find any support for DSB repair of mtDNA. Instead we observed a loss of the damaged mtDNA molecules and a severe decrease in mtDNA content. We demonstrate that none of the known mitochondrial nucleases are involved in the mtDNA degradation and that the DNA loss is not due to autophagy, mitophagy or apoptosis. Our study suggests that a still uncharacterized pathway for the targeted degradation of damaged mtDNA in a mitophagy/autophagy-independent manner is present in mitochondria, and might provide the main mechanism used by the cells to deal with DSBs.
线粒体DNA（mtDNA）可发生双链断裂（DSB），这是由复制缺陷或各种内源性或外源性因素引起的，如活性氧、化疗药物或电离辐射。mtDNA编码参与ATP生成的蛋白质，因此DSB后基因组完整性的维持至关重要。然而，DSB后mtDNA维持所涉及的机制仍不清楚。在本研究中，我们使用表达靶向线粒体的限制性内切酶PstI的人诱导细胞系统，研究了mtDNA DSB产生的后果。使用该系统，我们未发现任何支持mtDNA DSB修复的证据。相反，我们观察到受损mtDNA分子的丢失以及mtDNA含量的严重下降。我们证明，已知的线粒体核酸酶均不参与mtDNA的降解，且DNA的丢失并非由于自噬、线粒体自噬或凋亡。我们的研究表明，线粒体中存在一种仍未明确的途径，以不依赖线粒体自噬/自噬的方式靶向降解受损的mtDNA，这可能是细胞处理DSB的主要机制。
