Lipid signalling drives proteolytic rewiring of mitochondria by YME1L
Lipid signalling drives proteolytic rewiring of mitochondria by YME1L
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DOI：
10.1038/s41586-019-1738-6
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发表时间：
2019-11-14
期刊：
影响因子：
64.8
通讯作者：
Langer, Thomas
中科院分区：
文献类型：
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作者：
MacVicar, Thomas;Ohba, Yohsuke;Langer, Thomas
线粒体重编程为细胞提供了适应各种发育转变（例如干细胞激活或免疫细胞重编程）以及应对环境挑战（例如缺氧条件下或肿瘤发生过程中遇到的挑战）所需的代谢灵活性(1-3)。在这里，我们展示了 i-AAA 蛋白酶 YME1L 重新连接了先前存在的线粒体的蛋白质组，以响应缺氧或营养饥饿。抑制 mTORC1 可通过磷脂酸磷酸酶 LIPIN1 诱导脂质信号级联反应，从而降低线粒体膜中的磷脂酰乙醇胺水平并促进蛋白水解。 YME1L 降解线粒体蛋白转位酶、脂质转移蛋白和代谢酶，以急剧限制线粒体生物发生并支持细胞生长。 YME1L 介导的线粒体重塑支持胰腺导管腺癌细胞 (PDAC) 作为球体或异种移植物的生长。 PDAC 患者的肿瘤组织中也出现类似的线粒体蛋白质组变化，表明 YME1L 与这些肿瘤的病理生理学相关。我们的结果确定 mTORC1-LIPIN1-YME1L 轴是代谢和线粒体动力学之间界面线粒体蛋白质稳态的翻译后调节因子。
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 tumorigenesis(1-3). 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 mTORC1-LIPIN1-YME1L axis as a post-translational regulator of mitochondrial proteostasis at the interface between metabolism and mitochondrial dynamics.