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- Title
BNIP3-dependent mitophagy safeguards ESC genomic integrity via preventing oxidative stress-induced DNA damage and protecting homologous recombination.
- Authors
Zhao, Qian; Liu, Kun; Zhang, Lin; Li, Zheng; Wang, Liang; Cao, Jiani; Xu, Youqing; Zheng, Aihua; Chen, Quan; Zhao, Tongbiao
- Abstract
Embryonic stem cells (ESCs) have a significantly lower mutation load compared to somatic cells, but the mechanisms that guard genomic integrity in ESCs remain largely unknown. Here we show that BNIP3-dependent mitophagy protects genomic integrity in mouse ESCs. Deletion of Bnip3 increases cellular reactive oxygen species (ROS) and decreases ATP generation. Increased ROS in Bnip3−/− ESCs compromised self-renewal and were partially rescued by either NAC treatment or p53 depletion. The decreased cellular ATP in Bnip3−/− ESCs induced AMPK activation and deteriorated homologous recombination, leading to elevated mutation load during long-term propagation. Whereas activation of AMPK in X-ray-treated Bnip3+/+ ESCs dramatically ascended mutation rates, inactivation of AMPK in Bnip3−/− ESCs under X-ray stress remarkably decreased the mutation load. In addition, enhancement of BNIP3-dependent mitophagy during reprogramming markedly decreased mutation accumulation in established iPSCs. In conclusion, we demonstrated a novel pathway in which BNIP3-dependent mitophagy safeguards ESC genomic stability, and that could potentially be targeted to improve pluripotent stem cell genomic integrity for regenerative medicine.
- Publication
Cell Death & Disease, 2022, Vol 13, Issue 11, p1
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-022-05413-4