DELE1 tracks perturbed protein import and processing in human mitochondria.
DELE1 tracks perturbed protein import and processing in human mitochondria.
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DOI：
10.1038/s41467-022-29479-y
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发表时间：
2022-04-06
影响因子：
16.6
通讯作者：
Jae LT
中科院分区：
文献类型：
--
作者：
Fessler E;Krumwiede L;Jae LT
线粒体的蛋白质稳态控制是与年龄相关的疾病和有机体衰退的关键。然而，目前尚不清楚线粒体所经历的不同类型的压力如何在人类细胞中整合和适当地响应。在这里，我们确定在古老的保守的线粒体蛋白质进口和加工过程中的扰动作为DELE 1激活的来源：DELE 1是连续的跨线粒体膜到矩阵中，并检测不同类型的扰动沿着。转运中的DELE 1分子可以通过蛋白水解去除N-末端分选信号而被授权用于线粒体释放和应激信号传导。发生在线粒体表面的输入缺陷允许DELE 1前体结合并激活下游因子HRI，而不需要切割。全基因组遗传学揭示，DELE 1还响应于基质蛋白酶PITRM 1和MPP的受损前序列处理，这些蛋白酶在神经退行性疾病中突变。这些机制使DELE 1依赖的线粒体应激整合在人类系统中合理化，并可能为未来的神经病治疗提供信息。人类线粒体在神经系统疾病中经历大量的压力和功能障碍。在这里，作者揭示了DELE 1作为蛋白质输入和加工缺陷的多模式传感器，合理化线粒体应激整合。
Protein homeostatic control of mitochondria is key to age-related diseases and organismal decline. However, it is unknown how the diverse types of stress experienced by mitochondria can be integrated and appropriately responded to in human cells. Here we identify perturbations in the ancient conserved processes of mitochondrial protein import and processing as sources of DELE1 activation: DELE1 is continuously sorted across both mitochondrial membranes into the matrix and detects different types of perturbations along the way. DELE1 molecules in transit can become licensed for mitochondrial release and stress signaling through proteolytic removal of N-terminal sorting signals. Import defects that occur at the mitochondrial surface allow DELE1 precursors to bind and activate downstream factor HRI without the need for cleavage. Genome-wide genetics reveal that DELE1 additionally responds to compromised presequence processing by the matrix proteases PITRM1 and MPP, which are mutated in neurodegenerative diseases. These mechanisms rationalize DELE1-dependent mitochondrial stress integration in the human system and may inform future therapies of neuropathies. Human mitochondria experience substantial stress and malfunction in neurological diseases. Here, the authors reveal DELE1 as a multimodal sensor of protein import and processing defects, rationalizing mitochondrial stress integration.
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影响因子：
16.6
作者：
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DOI：
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发表时间：
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期刊：
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DOI：
10.1016/j.cub.2016.06.002
发表时间：
2016-08-08
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影响因子：
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影响因子：
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