小柯机器人

德国法兰克福大学大学Christian Münch研究组发现，一个细胞膜监视机制激活线粒体的UPR。2023年6月7日，《自然》在线发表了这项成果。

研究人员表明线粒体未折叠蛋白反应（UPR^mt）信号是由细胞液中两个单独的信号：线粒体活性氧（mtROS）和线粒体蛋白前体在细胞液中的积累（c-mtProt）驱动的。结合蛋白质组学和遗传学方法，研究人员发现线粒体错误折叠压力（MMS）会导致mtROS释放到细胞液中。同时，MMS导致线粒体蛋白导入缺陷，造成c-mtProt的积累。这两个信号整合起来激活UPR^mt；释放的mtROS氧化细胞膜HSP40蛋白DNAJA1，这导致细胞膜HSP70对c-mtProt的招募增强。因此，HSP70释放HSF1，后者转位到细胞核并激活UPR^mt基因的转录。

总之，研究人员确定了一个高度控制的细胞膜监视机制，它整合了独立的线粒体压力信号来启动UPR^mt。这些观察揭示了线粒体和细胞膜蛋白稳态之间的联系，并提供了对人类细胞中UPR^mt信号的分子见解。

据了解，UPR^mt对保护线粒体免受蛋白毒性损伤至关重要，它通过激活细胞核中的专用转录反应来恢复蛋白稳态。然而，目前仍不清楚MMS的信息如何作为人类UPR^mt的一部分被传递到细胞核。

附：英文原文

Title: A cytosolic surveillance mechanism activates the mitochondrial UPR

Author: Sutandy, F. X. Reymond, Gner, Ines, Tascher, Georg, Mnch, Christian

Issue&Volume: 2023-06-07

Abstract: The mitochondrial unfolded protein response (UPRmt) is essential to safeguard mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis1,2. Yet, it remains unclear how the information on mitochondria misfolding stress (MMS) is signalled to the nucleus as part of the human UPRmt (refs. 3,4). Here, we show that UPRmt signalling is driven by the release of two individual signals in the cytosol—mitochondrial reactive oxygen species (mtROS) and accumulation of mitochondrial protein precursors in the cytosol (c-mtProt). Combining proteomics and genetic approaches, we identified that MMS causes the release of mtROS into the cytosol. In parallel, MMS leads to mitochondrial protein import defects causing c-mtProt accumulation. Both signals integrate to activate the UPRmt; released mtROS oxidize the cytosolic HSP40 protein DNAJA1, which leads to enhanced recruitment of cytosolic HSP70 to c-mtProt. Consequently, HSP70 releases HSF1, which translocates to the nucleus and activates transcription of UPRmt genes. Together, we identify a highly controlled cytosolic surveillance mechanism that integrates independent mitochondrial stress signals to initiate the UPRmt. These observations reveal a link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPRmt signalling in human cells.

DOI: 10.1038/s41586-023-06142-0

Source: https://www.nature.com/articles/s41586-023-06142-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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