通过线粒体ROS依赖的BCAA代谢,Irf4参与诱导的造血衰老
Ziyan Liu1, Jingyu Wang1, Wei Zhang1
1Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environment and Aging, Capital Medical University, Beijing 100069, PR China.
暴露会通过增加Irf4引起细胞衰老和造血损伤,这会破坏分支链氨基酸代谢. 抑制Irf4或补充氨基酸可以防止这种损伤.
科学领域:
- 血液学
- 毒理学
- 细胞衰老
背景情况:
- 衰老的造血干细胞 (HSPC) 的积累会导致造血损伤.
- 是一种与HSPC损伤相关的人类致癌物,但其在环境剂量中诱导细胞衰老的作用尚不清楚.
研究的目的:
- 调查环境中的剂是否通过细胞衰老诱导HSPC损伤.
- 阐明引起的造血损伤的分子机制.
主要方法:
- 使用了体内 (暴露于蒸汽的C57BL/6J小鼠) 和体内 (暴露于1,4-BQ的FDC-P1细胞) 模型.
- 使用单细胞RNA测序,蛋白质组学和生物化学测试.
- 测试了干扰素调节因子4 (Irf4) 抑制和分支链氨基酸 (BCAA) 补充剂.
主要成果:
- 及其代谢物诱导骨髓和造血细胞的衰老.
- 暴露上调了Irf4,被确定为衰老和损伤的关键媒介.
- 破坏了BCAA代谢,增加了Bcat1和Bckdh活动,导致线粒体氧化应激.
结论:
- 通过过度的BCAAs代谢和线粒体损伤,Irf4引发了诱导的造血前代细胞衰老和损伤.
- 针对Irf4或调节BCAA代谢为中毒提供了潜在的治疗策略.
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