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通过输入错误折叠的蛋白质到线粒体中的细胞质蛋白质稳定

Linhao Ruan^1,2, Chuankai Zhou³, Erli Jin²

¹Center for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, USA.

|February 28, 2017

概括

错误折叠的蛋白质被导入线粒体进行降解,这一过程被称为MAGIC (线粒体作为细胞质中守护者). 这种机制有助于在衰老和神经退行过程中管理蛋白质聚合物和线粒体健康.

科学领域:

细胞生物学
分子生物学
老龄化研究

背景情况:

由蛋白质聚合物和线粒体功能障碍所标志的蛋白质稳定性损失是衰老和神经退行的主要原因.
线粒体功能障碍与蛋白质聚合之间的关系尚未完全理解.
细胞质蛋白聚合物通常被保留在母细胞中,与线粒体联系在一起,Hsp104有助于它们的清除.

研究的目的:

研究线粒体在控制细胞质蛋白聚合和蛋白质稳定中的作用.
阐明蛋白质聚合,线粒体进口和降解之间的机制.
要确定这种线粒体介导的蛋白质稳定机制是否在人体细胞中保持.

主要方法:

使用芽生长酵母作为研究蛋白质聚合和线粒体进口的模型系统.
在热冲击条件下分析蛋白质聚合物,检查它们与线粒体进口机械的相互作用.
研究了阻断线粒体进口和蛋白质酶活性对聚合物降解的影响.
评估了细胞质Hsp70s在蛋白质进口到线粒体中的作用.

主要成果:

容易聚合的细胞质蛋白被输入线粒体以进行降解.
热冲击诱导的蛋白质聚合物与线粒体进口复合物相互作用,而易聚合的蛋白质进入线粒体区.
线粒体进口机械和蛋白酶对于及时的聚合物溶解至关重要;阻断进口延迟了降解.
细胞质Hsp70s的缺陷增加了蛋白质错误进入线粒体,导致线粒体压力增加.

结论:

确定了一种新的线粒体介导蛋白质稳定机制,称为MAGIC (线粒体作为细胞质中守护者),其中线粒体降解聚合的细胞质蛋白质.
这种机制需要线粒体进口机械和蛋白质酶,并且与蛋白质体降解不同.
证据表明MAGIC途径可能在人体细胞中保留,为与年龄相关的和神经退行性疾病提供新的治疗点.

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