Department of Pathology and Programs in Cancer Biology and Neurosciences, Stanford University School of Medicine, Stanford, CA, USA.
Department of Pathology and Programs in Cancer Biology and Neurosciences, Stanford University School of Medicine, Stanford, CA, USA; Department of Cancer Biology, Genentech Inc., South San Francisco, CA, USA.
Mol Cell. 2019 Aug 22;75(4):835-848.e8. doi: 10.1016/j.molcel.2019.06.031. Epub 2019 Aug 1.
Mitochondrial dysfunction and proteostasis failure frequently coexist as hallmarks of neurodegenerative disease. How these pathologies are related is not well understood. Here, we describe a phenomenon termed MISTERMINATE (mitochondrial-stress-induced translational termination impairment and protein carboxyl terminal extension), which mechanistically links mitochondrial dysfunction with proteostasis failure. We show that mitochondrial dysfunction impairs translational termination of nuclear-encoded mitochondrial mRNAs, including complex-I 30kD subunit (C-I30) mRNA, occurring on the mitochondrial surface in Drosophila and mammalian cells. Ribosomes stalled at the normal stop codon continue to add to the C terminus of C-I30 certain amino acids non-coded by mRNA template. C-terminally extended C-I30 is toxic when assembled into C-I and forms aggregates in the cytosol. Enhancing co-translational quality control prevents C-I30 C-terminal extension and rescues mitochondrial and neuromuscular degeneration in a Parkinson's disease model. These findings emphasize the importance of efficient translation termination and reveal unexpected link between mitochondrial health and proteome homeostasis mediated by MISTERMINATE.
线粒体功能障碍和蛋白质稳态失效常作为神经退行性疾病的标志性特征而共同存在。但人们对这两种病理学之间的关系还不甚了解。在这里，我们描述了一种称为 MISTERMINATE（线粒体应激诱导的翻译终止障碍和蛋白质羧基末端延伸）的现象，它从机制上把线粒体功能障碍与蛋白质稳态失效联系起来。我们发现，线粒体功能障碍会损害核编码的线粒体 mRNA 的翻译终止，包括在果蝇和哺乳动物细胞中线粒体表面的复合物 I 30kD 亚基（C-I30）mRNA。在正常终止密码子处停滞的核糖体继续在 C-I30 的 C 末端添加某些非 mRNA 模板编码的氨基酸。C 末端延伸的 C-I30 组装成 C-I 时具有毒性，并在细胞质中形成聚集体。增强共翻译质量控制可防止 C-I30 的 C 末端延伸，并可挽救帕金森病模型中的线粒体和神经肌肉退化。这些发现强调了有效翻译终止的重要性，并揭示了由 MISTERMINATE 介导的线粒体健康与蛋白质组稳态之间的意外联系。
