Laboratory of Mitochondrial Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, 565-0871, Japan.
Laboratory of Mitochondrial Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, 565-0871, Japan.
Biochem Biophys Res Commun. 2018 Jul 7;502(1):76-83. doi: 10.1016/j.bbrc.2018.05.123. Epub 2018 May 24.
Mitophagy is an evolutionarily conserved autophagy process that selectively degrades mitochondria. This catabolic event is considered to be a mitochondrial quality control system crucial for cell homeostasis, however, mechanisms regulating mitophagy remain largely unknown. Here we show that the TORC1 (target of rapamycin complex 1) signaling pathway regulates mitophagy in budding yeast via SEACIT (Seh1-associated complex inhibiting TORC1) consisting of Iml1, Npr2, and Npr3. Cells lacking SEACIT displayed significant reductions in mitophagy during prolonged respiratory growth, while the other selective autophagy processes are less affected. Under the same conditions, mitophagy defects were strikingly rescued in the SEACIT mutants (1) treated with rapamycin, a specific TOR kinase inhibitor, (2) lacking Gtr1, a TORC1-stimulating Rag family GTPase downstream of SEACIT, and (3) devoid of Pib2, a phosphatidylinositol 3-phosphate-binding TORC1 activator. Notably, loss of Npr2 exacerbated mitophagy defects in cells lacking Atg13, a TORC1 effector crucial for activation of autophagy-related processes, suggesting additional mitophagy-specific regulator(s) downstream of TORC1. Finally, we found that npr2-null cells failed to stabilize the interaction of Atg32 with Atg11, a scaffold protein essential for mitophagy. Collectively, our data implicate SEACIT-mediated inactivation of TORC1 signaling as a critical step to promote respiration-induced mitophagy.
线粒体自噬是一种进化上保守的自噬过程，它选择性地降解线粒体。这种分解代谢事件被认为是一种至关重要的线粒体质量控制系统，对于细胞内稳态至关重要，但是，调节线粒体自噬的机制在很大程度上仍然未知。在这里，我们表明 TORC1（雷帕霉素复合物 1 的靶点）信号通路通过 SEACIT（由 Iml1、Npr2 和 Npr3 组成的 Seh1 相关复合物抑制 TORC1）调节芽殖酵母中的线粒体自噬。缺乏 SEACIT 的细胞在长时间呼吸生长过程中表现出明显减少的线粒体自噬，而其他选择性自噬过程的影响较小。在相同条件下，SEACIT 突变体（1）用雷帕霉素处理，一种特定的 TOR 激酶抑制剂，（2）缺乏 Gtr1，SEACIT 下游的 TORC1 刺激 Rag 家族 GTPase，和（3）缺乏 Pib2，一种结合 TORC1 的磷酸肌醇 3-磷酸结合 TORC1 激活剂，线粒体自噬缺陷得到显著挽救。值得注意的是，缺失 Npr2 加剧了缺乏 Atg13 的细胞中线粒体自噬缺陷，Atg13 是一种对于激活与自噬相关过程至关重要的 TORC1 效应物，这表明 TORC1 下游存在额外的线粒体自噬特异性调节因子。最后，我们发现 npr2 缺失细胞无法稳定 Atg32 与 Atg11 的相互作用，Atg11 是线粒体自噬所必需的支架蛋白。总之，我们的数据表明 SEACIT 介导的 TORC1 信号失活是促进呼吸诱导的线粒体自噬的关键步骤。
