The master energy sensor AMPK-1α regulates the expression of various autophagic and mitochondrial respiratory elements in T cell memory

AMPK-1α is a master energy sensor that phosphorylates more than 100 client proteins involved in almost all branches of cellular metabolism. We recently demonstrated that weak mTORC1 (mTORC1Weak) signaling promotes the differentiation of pro-survival cytokine IL-7- or IL-15-stimulated CD8+ memory T (IL-7/TM and IL-15/TM) cells derived from ovalbumin (OVA)-specific T-cell receptor transgenic OTI mice by upregulating the expression of AMPK-1α and another twelve autophagic and metabolic regulators, including ULK1, ATG7, LC3II, SIRT1, PGC1α, CPT1α, AQP9, Complex I, LAL, OPA1, Bcl6, and TFAM. To investigate the potential role of AMPK-1α in controlling the abundance of these proteins, we genetically engineered AMPK knockout (KO)/OTI mice, and then prepared and subjected IL-7/TM or IL-15/TM cells from these animals to western blot analyses. Interestingly, we found that their steady-state levels were all significantly down-regulated in both IL-7/TM and IL-15/TM cells upon the loss of AMPK-1α expression. Thus, our data suggest that AMPK-1α indeed regulates these 12 downstream targets, a possibility that is further substantiated by the fact that a modern chemical genetic screen previously identified ULK1, ATG7, LC3II, SERT1, and PGC1α as AMPK-1α substrates. Taken together, our data establishes that the master energy sensor AMPK-1α controls the expression of seven additional regulatory markers, which are all critical to cellular metabolism and whose identification may impact the development of AMPK-1α-targeted therapeutics for treating metabolic disorders and cancer diseases.