线粒体YME1L1控制着未被占用的蛋白转位酶通道
Meng-Chieh Hsu1,2, Hiroki Kinefuchi3,4, Linlin Lei1
1Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Nature cell biology
|January 8, 2025
概括
线粒体进口阻塞触发YME1L1蛋白酶活性,降解TIM23组件. 当蛋白质进口受损时,这种YME1L1功能对细胞生长和线粒体质量控制至关重要.
科学领域:
- 线粒体生物学 线粒体生物学
- 蜂质量控制机制 蜂质量控制机制
- 蛋白质进口途径 蛋白质进口途径
背景情况:
- 线粒体蛋白质的进口对于细胞功能和生物发生是必不可少的.
- 细胞对受损的线粒体进口的反应对于维持恒常状态至关重要.
- 外膜转位酶 (TOM) 和内膜转位酶 (TIM) 综合体促进蛋白质转位.
研究的目的:
- 为了研究细胞对受损的线粒体蛋白质的反应.
- 阐明特定蛋白酶和蛋白质复合体在线粒体质量控制中的作用.
- 开发一种哺乳动物系统来阻断线粒体蛋白质进口.
主要方法:
- 开发一种哺乳动物进口阻断系统,使用与MIC60.0合的二叶酸减少酶来阻断进口.
- 通过双叶酸还原酶域的美托特雷克萨特稳定抑制线粒体蛋白质进口.
- 分析ATF4激活,ATAD1表达,VCP/p97抑制和YME1L1活动.
- 评估细胞生长缺陷和YME1L1损失的影响.
主要成果:
- 阻断线粒体进口并没有激活ATF4或对ATAD1/VCP/p97.7作出反应.
- 插入外膜通道的转位酶诱导YME1L1降解内膜转位酶的TIMM17A和TIMM23组件.
- 无人居住的TIM23综合体暴露了YME1L1.1.认可的污染.
- 进口封锁导致细胞生长缺陷,由YME1L1损失加剧.
结论:
- YME1L1蛋白酶通过降解未被占用的TIM23通道组件,在线粒体质量控制中发挥关键作用.
- YME1L1的活性提供了对因线粒体蛋白质进口受损引起的细胞生长抑制的保护作用.
- 这些发现突出了在压力条件下维护线粒体完整性的新机制.
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