Fig. 7: Models of how mitochondrial stress and ER stress activate mechanistically different pathways, involving the lysosomes, v-ATPase/mTORC1, ATF4, and/or ribosomes, to concordantly activate the UPR^mt and the UPR^ER.

Left: in response to mitochondrial stress, mTORC1 is activated at the lysosomal surface and EIF2α phosphorylation is mildly increased, leading to a moderate increase in ATF4 translation. Meanwhile, activated mTORC1 directly phosphorylates ATF4, leading to increased ATF4 binding to the promoters of UPR^mt genes and UPR^mt activation. Right: in response to ER stress, mTORC1 activity is suppressed but the EIF2α phosphorylation is robustly increased, leading to an increase in translation and nuclear accumulation of ATF4, and to the subsequent activation of the ER UPR (UPR^ER). CQ chloroquine, ConA/BafA1 Concanamycin A/Bafilomycin A1.