BNIP3-dependent mitophagy safeguards ESC genomic integrity via preventing oxidative stress-induced DNA damage and protecting homologous recombination.
Qian ZhaoKun LiuLin ZhangZheng LiLiang WangJiani CaoYouqing XuAihua ZhengQuan ChenTong-Biao ZhaoPublished in: Cell death & disease (2022)
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.
Keyphrases
- dna damage
- dna repair
- copy number
- reactive oxygen species
- stem cells
- cell death
- oxidative stress
- nlrp inflammasome
- high resolution
- computed tomography
- magnetic resonance imaging
- induced apoptosis
- transcription factor
- gene expression
- magnetic resonance
- mass spectrometry
- cell proliferation
- mesenchymal stem cells
- cell cycle arrest
- protein kinase
- high glucose
- signaling pathway
- smoking cessation
- newly diagnosed