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1000
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Abstract/Summary
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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.
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