@article{868f6939f2db4b468e83e58edf49953b,
title = "Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation",
abstract = "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 (UPRmt). 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 UPRmt, but not other similar stress responses, such as the UPRER. 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 UPRmt activation and mitochondrial function resilience.",
author = "Li, {Terytty Yang} and Qi Wang and Gao, {Arwen W.} and Xiaoxu Li and Yu Sun and Adrienne Mottis and Minho Shong and Johan Auwerx",
note = "Funding Information: We thank D. Ron (Cambridge Institute for Medical Research) for providing the Atf4 MEFs. We thank all members of J. Auwerx and K. Schoonjans laboratories for helpful discussions. We thank the Imaging platform at the Shanghai Key Laboratory of Metabolic Remodeling and Health, Fudan University for technical assistances. This work was supported by grants from the Ecole Polytechnique Federale de Lausanne (EPFL), the European Research Council (ERC-AdG-787702), the Swiss National Science Foundation (SNSF 31003A_179435), GRL grant of the National Research Foundation of Korea (NRF 2017K1A1A2013124) and Fudan University (JIH2313035Y). T.Y.L. was supported by the {"}Human Frontier Science Program{"} (LT000731/2018-L). Q.W. was supported by the European Molecular Biology Organization (ALTF 111-2021). A.W.G. was supported by the Accelerator prize given by the United Mitochondrial Disease Foundation (PF-19-0232). X.L. was supported by the China Scholarship Council (201906050019). −/− Publisher Copyright: {\textcopyright} 2023, Center for Excellence in Molecular Cell Science, CAS.",
year = "2023",
month = dec,
doi = "https://doi.org/10.1038/s41421-023-00589-1",
language = "English",
volume = "9",
journal = "Cell discovery",
issn = "2056-5968",
publisher = "Nature Publishing Group",
number = "1",
}