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 (UPR^mt). 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^mt, but not other similar str

SUBMITTER: Li TY 

PROVIDER: S-EPMC10484937 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature