Li Terytty Yang, Wang Qi, Gao Arwen W, Li Xiaoxu, Sun Yu, Mottis Adrienne, Shong Minho, Auwerx Johan
State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling and Health, Laboratory of Longevity and Metabolic Adaptations, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Cell Discov. 2023 Sep 7;9(1):92. doi: 10.1038/s41421-023-00589-1.
Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPR). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPR, but not other similar stress responses, such as the UPR. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from ROS-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPR activation and mitochondrial function resilience.
溶酶体不仅是大分子降解的核心平台，也是多种信号通路整合的核心平台。然而，溶酶体是否以及如何介导线粒体应激反应（MSR）在很大程度上仍不清楚。在这里，我们证明通过液泡H-ATP酶（v-ATP酶）进行的溶酶体酸化对于线粒体未折叠蛋白反应（UPR）的转录激活至关重要。线粒体应激刺激v-ATP酶介导的雷帕霉素复合物1（mTORC1）的溶酶体激活，然后mTORC1直接磷酸化MSR转录因子——激活转录因子4（ATF4）。mTORC1依赖性ATF4磷酸化的破坏会阻断UPR，但不会阻断其他类似的应激反应，如UPR。最后，v-ATP酶/mTORC1信号下游的ATF4磷酸化对于维持线粒体氧化还原稳态以及保护细胞免受线粒体应激时与活性氧（ROS）相关的细胞死亡至关重要。因此，v-ATP酶/mTORC1通过溶酶体介导的ATF4磷酸化将线粒体应激与UPR激活和线粒体功能恢复联系起来。
