| First Author | Mao Y | Year | 2026 |
| Journal | Cell Metab | Volume | 38 |
| Issue | 1 | Pages | 192-207.e8 |
| PubMed ID | 41061696 | Mgi Jnum | J:377422 |
| Mgi Id | MGI:8275851 | Doi | 10.1016/j.cmet.2025.09.004 |
| Citation | Mao Y, et al. (2026) AMPKalpha2 signals amino acid insufficiency to inhibit protein synthesis. Cell Metab 38(1):192-207.e8 |
| abstractText | The functional difference between the two catalytic subunits, alpha1 and alpha2, of AMP-activated protein kinase (AMPK) complexes remains elusive. Herein, we report that AMPKalpha2 specifically transduces amino acid insufficiency signals to protein synthesis. Low amino acid levels, high protein levels, and reduced phosphorylation of AMPKalpha threonine 172 (p-T172) are observed in blood samples in patients with Alzheimer's disease (AD) from a cohort of 1,000,000 Chinese individuals. Loss of alpha2, but not alpha1, recaptures these observations and induces AD-like cognitive dysfunction in mice. Mechanistically, low amino acid-activated general control nonderepressible 2 (GCN2) specifically phosphorylates alpha2 at T172 independent of AMP and fructose 1,6-bisphosphate to inhibit protein synthesis. alpha2-p-T172 loss renders protein over-synthesis and AD-pathologic protein aggregation in cells and in mouse brain. AMPK activators metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), as well as branched-chain amino acid (BCAA) or protein restriction, alpha2-p-T172-dependently prevent AD-like symptoms in mice. We identify AMPKalpha2 as a specific amino acid abundance detector for protein synthesis. |
