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脂质信号可重塑线粒体蛋白质组
2019-11-07 14:26

德国马普衰老生物学研究所Thomas Langer课题组取得一项新进展。他们发现脂质信号通过YME1L蛋白驱动线粒体的蛋白组重塑。2019年11月6日,《自然》杂志在线发表了这项成果。

研究人员发现,i-AAA蛋白酶YME1L能够重连线粒体中的蛋白质组,以应对缺氧或营养不足的情况。抑制mTORC1可通过磷脂酸磷酸酶LIPIN1诱导脂质信号传导级联反应,从而降低线粒体膜中磷脂酰乙醇胺的水平并促进蛋白水解。YME1L降解线粒体蛋白的转位酶、脂质转移蛋白和代谢酶,从而严重限制线粒体生成并支持细胞生长。

YME1L介导的线粒体重塑支持以球状体或异种移植物的形式生长的胰腺导管腺癌(PDAC)细胞。PDAC患者的肿瘤组织中线粒体蛋白质组发生类似变化,这表明YME1L与这些肿瘤的病理生理学有关。

这些研究结果表明,mTORC1–LIPIN1–YME1L信号轴在代谢和线粒体动力学之间的界面上是线粒体蛋白稳态的翻译后调节者。

据悉,线粒体的重编程为细胞提供了适应各种发育过渡(例如干细胞激活或免疫细胞重编程)并应对环境挑战(例如在低氧条件下或在肿瘤发生过程中遇到的挑战)所需的代谢灵活性。

附:英文原文

Title: Lipid signalling drives proteolytic rewiring of mitochondria by YME1L

Author: Thomas MacVicar, Yohsuke Ohba, Hendrik Nolte, Fiona Carola Mayer, Takashi Tatsuta, Hans-Georg Sprenger, Barbara Lindner, Yue Zhao, Jiahui Li, Christiane Bruns, Marcus Krger, Markus Habich, Jan Riemer, Robin Schwarzer, Manolis Pasparakis, Sinika Henschke, Jens C. Brning, Nicola Zamboni, Thomas Langer

Issue&Volume: 2019-11-06

Abstract: Reprogramming of mitochondria provides cells with the metabolic flexibility required to adapt to various developmental transitions such as stem cell activation or immune cell reprogramming, and to respond to environmental challenges such as those encountered under hypoxic conditions or during tumorigenesis13. Here we show that the i-AAA protease YME1L rewires the proteome of pre-existing mitochondria in response to hypoxia or nutrient starvation. Inhibition of mTORC1 induces a lipid signalling cascade via the phosphatidic acid phosphatase LIPIN1, which decreases phosphatidylethanolamine levels in mitochondrial membranes and promotes proteolysis. YME1L degrades mitochondrial protein translocases, lipid transfer proteins and metabolic enzymes to acutely limit mitochondrial biogenesis and support cell growth. YME1L-mediated mitochondrial reshaping supports the growth of pancreatic ductal adenocarcinoma (PDAC) cells as spheroids or xenografts. Similar changes to the mitochondrial proteome occur in the tumour tissues of patients with PDAC, suggesting that YME1L is relevant to the pathophysiology of these tumours. Our results identify the mTORC1LIPIN1YME1L axis as a post-translational regulator of mitochondrial proteostasis at the interface between metabolism and mitochondrial dynamics. Under conditions such as hypoxia or starvation, an mTORC1-lipid signalling pathway initiates mitochondrial proteolysis by YME1L.

DOI: 10.1038/s41586-019-1738-6

Source: https://www.nature.com/articles/s41586-019-1738-6

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
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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