近日，美国国立卫生研究院Richard J. Youle等研究人员合作发现，线粒体YME1L1调控未占据的蛋白转位酶通道。该研究于2025年1月7日在线发表于国际一流学术期刊《自然—细胞生物学》。

研究人员开发了一种哺乳动物导入阻断系统，该系统通过将二氢叶酸还原酶与内膜蛋白MIC60的氨基末端融合来实现。尽管通过甲氨蝶呤稳定二氢叶酸还原酶域会抑制内源性线粒体蛋白导入，但这既未激活转录因子ATF4，也未受ATAD1表达或VCP/p97抑制的影响。另一方面，值得注意的是，封闭外膜转位酶通道会诱导ATP依赖性蛋白酶YME1L1，促使其清除内膜转位酶（TIM23）通道的组分TIMM17A和TIMM23。

数据表明，未占据的TIM23复合物暴露了TIMM17A的C末端降解信号（degron），使其被YME1L1降解。封闭通道会导致细胞生长缺陷，并且YME1L1的缺失会加剧生长抑制，这显示了YME1L1活性的保护作用。YME1L1似乎在线粒体质量控制中发挥着至关重要的作用，以对抗外膜转位酶复合物中前体蛋白的停滞和未占据的TIM23通道。

据介绍，线粒体蛋白质通过外膜和内膜的导入是线粒体生物发生的关键。近期研究探讨了当蛋白质导入受到各种不同损伤影响时，细胞是如何应对的。

附：英文原文

Title: Mitochondrial YME1L1 governs unoccupied protein translocase channels

Author: Hsu, Meng-Chieh, Kinefuchi, Hiroki, Lei, Linlin, Kikuchi, Reika, Yamano, Koji, Youle, Richard J.

Issue&Volume: 2025-01-07

Abstract: Mitochondrial protein import through the outer and inner membranes is key to mitochondrial biogenesis. Recent studies have explored how cells respond when import is impaired by a variety of different insults. Here, we developed a mammalian import blocking system using dihydrofolate reductase fused to the N terminus of the inner membrane protein MIC60. While stabilization of the dihydrofolate reductase domain by methotrexate inhibited endogenous mitochondrial protein import, it neither activated the transcription factor ATF4, nor was affected by ATAD1 expression or by VCP/p97 inhibition. On the other hand, notably, plugging the channel of translocase of the outer membrane) induced YME1L1, an ATP-dependent protease, to eliminate translocase of the inner membrane (TIM23) channel components TIMM17A and TIMM23. The data suggest that unoccupied TIM23 complexes expose a C-terminal degron on TIMM17A to YME1L1 for degradation. Import plugging caused a cell growth defect and loss of YME1L1 exacerbated the growth inhibition, showing the protective effect of YME1L1 activity. YME1L1 seems to play a crucial role in mitochondrial quality control to counteract precursor stalling in the translocase of the outer membrane complex and unoccupied TIM23 channels.

DOI: 10.1038/s41556-024-01571-z

Source: https://www.nature.com/articles/s41556-024-01571-z