An Early mtUPR: Redistribution of the Nuclear Transcription Factor Rox1 to Mitochondria Protects against Intramitochondrial Proteotoxic Aggregates
An Early mtUPR: Redistribution of the Nuclear Transcription Factor Rox1 to Mitochondria Protects against Intramitochondrial Proteotoxic Aggregates
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DOI：
10.1016/j.molcel.2019.09.026
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发表时间：
2020-01
期刊：
影响因子：
16
通讯作者：
Daniel Poveda-Huertes;Stanka Matic;Adinarayana Marada;L. Habernig;Mariya Licheva;Lisa Myketin;R. Gilsbach;Sergi Tosal-Castano;Daniel Papinski;Patrycja Mulica;O. Kretz;Cansu Küçükköse;A. A. Taskin-A.;L. Hein;C. Kraft;S. Büttner;C. Meisinger;F. Vögtle
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作者：
Daniel Poveda-Huertes;Stanka Matic;Adinarayana Marada;L. Habernig;Mariya Licheva;Lisa Myketin;R. Gilsbach;Sergi Tosal-Castano;Daniel Papinski;Patrycja Mulica;O. Kretz;Cansu Küçükköse;A. A. Taskin-A.;L. Hein;C. Kraft;S. Büttner;C. Meisinger;F. Vögtle
线粒体蛋白质组主要通过输入核编码的前体来构建，这些前体主要由可裂解的前序列靶向。导入后的前序列处理对于蛋白质稳态和存活是必不可少的，但功能失调的蛋白质成熟的后果尚不清楚。我们发现受损的前序列处理导致线粒体内前体的积累，形成聚集体，从而逃避降解，并且出乎意料地不会导致细胞死亡。相反，细胞通过激活线粒体未折叠蛋白反应（mtUPR）样途径存活，该途径在前体积累后很早就被触发。与经典的应激途径相反，这种即时反应通过核HMG盒转录因子Rox1易位到线粒体来维持线粒体蛋白的输入、膜电位和翻译。Rox1结合mtDNA，并执行TFAM样功能，对转录和翻译至关重要。早期mtUPR的诱导提供了一个可逆的应激模型，以应激TFAM Rox1作为第一道防线，从机制上剖析mtUPR通路的初始步骤。
The mitochondrial proteome is built mainly by import of nuclear-encoded precursors, which are targeted mostly by cleavable presequences. Presequence processing upon import is essential for proteostasis and survival, but the consequences of dysfunctional protein maturation are unknown. We find that impaired presequence processing causes accumulation of precursors inside mitochondria that form aggregates, which escape degradation and unexpectedly do not cause cell death. Instead, cells survive via activation of a mitochondrial unfolded protein response (mtUPR)-like pathway that is triggered very early after precursor accumulation. In contrast to classical stress pathways, this immediate response maintains mitochondrial protein import, membrane potential, and translation through translocation of the nuclear HMG-box transcription factor Rox1 to mitochondria. Rox1 binds mtDNA and performs a TFAM-like function pivotal for transcription and translation. Induction of early mtUPR provides a reversible stress model to mechanistically dissect the initial steps in mtUPR pathways with thestressTFAM Rox1 as the first line of defense.