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

Michelle Yu; Zhaojia Wu; Scot C. Leary; Jim Xiang; Michelle Yu; Zhaojia Wu; Scot C. Leary; Jim Xiang

doi:10.3934/molsci.2025012

AIMS Molecular Science

2025, Volume 12, Issue 2: 187-197. doi: 10.3934/molsci.2025012

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Commentary

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

1.
Research Unit, Saskatchewan Cancer Agency, 20 Campus Drive, Saskatoon, Saskatchewan S7N 4H4, Canada
2.
Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
3.
Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
These authors contributed equally to this work.

Received: 11 March 2025 Revised: 05 June 2025 Accepted: 18 June 2025 Published: 24 June 2025

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 (mTORC1^Weak) signaling promotes the differentiation of pro-survival cytokine IL-7- or IL-15-stimulated CD8⁺ memory T (IL-7/T_M and IL-15/T_M) 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/T_M or IL-15/T_M 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/T_M and IL-15/T_M 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.
- AMPK-1α,
- autophagy,
- cell metabolism,
- T cell memory,
- western blotting
Citation: Michelle Yu, Zhaojia Wu, Scot C. Leary, Jim Xiang. The master energy sensor AMPK-1α regulates the expression of various autophagic and mitochondrial respiratory elements in T cell memory[J]. AIMS Molecular Science, 2025, 12(2): 187-197. doi: 10.3934/molsci.2025012

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Abstract

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 (mTORC1^Weak) signaling promotes the differentiation of pro-survival cytokine IL-7- or IL-15-stimulated CD8⁺ memory T (IL-7/T_M and IL-15/T_M) 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/T_M or IL-15/T_M 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/T_M and IL-15/T_M 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.

Abbreviations

ADP

adenosine diphosphate

AMPK-1α

adenosine monophosphate-activated protein kinase-1α

APC

antigen-presenting cells

AQP9

aquaporin-9

ATG7

autophagy-related gene-7

ATP

adenosine triphosphate

CaMKK2

Ca⁺⁺/calmodulin-activated protein kinase kinase-2

CPT1α

carnitine palmitoyl transferase-1α

DRP1

dynamin-related protein-1

FAO

fatty-acid oxidation

FOXO1

forkhead box-O-1

HIF-1α

hypoxia-inducible factor-1α

ID3

DNA binding-3

JAK3

Janus kinase-3

KLRG1

killer cell lectin-like receptor subfamily G member-1

LAL

lysosomal acid lipase

LC3II

microtubule-associated protein light chain-3 II

LKB1

liver kinase-B1

mTORC1

mammalian target of rapamycin complex-1

NF-κB

nuclear factor kappa B

OPA

optic atrophy-1

OVA

ovalbumin

PCG1α

PPARγ coactivator-1α

PKA

cyclic AMP-activated protein kinase A

PPARγ

peroxisome proliferator-activated receptor γ

SIRT

silent information regulator of transcription-1

SOD

superoxide dismutase

TAK-1

TGF-β-activated kinase-1

TCF1

T cell factor-1

TCR

T-cell receptor

T_E

effector T

T_M

memory T

T_n

naïve T

TSC2

tuberous aclerosis-2

UCP2

uncoupling protein-2

ULK1

Unc-51-like autophagy-activating kinase-1

wild-type

Acknowledgments

This work was supported by a research grant (#PJT153314) from the Canadian Institutes of Health Research (CIHR) for JX.

Conflicts of interest

The authors declare that they have no conflicts of interest.

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