AMPK and the PI3K-mTORC2-AKT Axis Shape the Mitochondrial Integrated-Stress-Response

Abstract

The integrated-stress-response (ISR) and AMPK are core regulators of adaptive mammalian biology. Here, we examined how mitochondrial stress connects with the ISR (mt-ISR), the mTORC1-eIF4F translation apparatus and if/how concurrent AMPK activation controls this signalling circuit. We show inhibited electron-transfer-chain (ETC) activity, and a hyper-fission mitochondrial morphology, stimulated potent ISR/ATF4-driven adaption whilst preserving mTORC1-eIF4F activity, even in the presence of activated AMPK. The mTORC1-eIF4F axis was essential to execute the ATF4-adaptive response during mt-ISR, and mTORC1 activity was preserved by concurrent PI3K-mTORC2-AKT induction; eIF4F, mTORC1, PI3K and AKT inhibitors preclude upregulation of ATF4 and a panel of ATF4 target-proteins, including the pro-proliferative mitochondria-residing SHMT2-PCK2-MTHFD2 triad. AMPK expression was also essential to orchestrate ATF4 signalling during mt-ISR by preserving S6K1 activity, and thus eIF4F-mediated translation. Our study now positions the PI3K-mTORC2-AKT-mTORC1-eIF4F signalling relay as critical mt-ISR apparatus. Finally, our study challenges the importance of ISR to adaptive recovery during mitochondrial damage in cells; proliferation in ETC-inhibited cells required AMPK but not ATF4 nor eIF2α phosphorylation. The interplay between mitochondrial stress, mTORC1, ISR and AMPK in adaptive biology are discussed accordingly.