AMPK (AMP-activated protein kinase)

Classification

Category: Upstream regulator (energy-sensing kinase)

Aliases: 5' AMP-activated protein kinase

Relationship to mTOR complexes: Upstream of mTORC1 (energy-status branch); inhibits mTORC1 — see mTORC1 vs mTORC2 for the full complex-level map.

Summary

AMPK is the cell's principal energy-status sensor, activated by a rising AMP:ATP or ADP:ATP ratio (low cellular energy). Once active, AMPK inhibits mTORC1 through two routes: directly phosphorylating and activating TSC2 (reinforcing the TSC1/2 brake on Rheb), and directly phosphorylating RPTOR (the mTORC1 scaffold). Metformin's mTOR-adjacent classification in this dataset stems from its AMPK-activating mechanism.

• Rising AMP:ATP/ADP:ATP ratio (low cellular energy, e.g. exercise, caloric restriction, fasting) activates AMPK
• Metformin activates AMPK indirectly via mitochondrial complex I inhibition -- see /metformin

• Phosphorylates and activates TSC2, reinforcing inhibition of Rheb/mTORC1
• Directly phosphorylates RPTOR (mTORC1 scaffold), independently inhibiting mTORC1
• Promotes catabolic, energy-generating processes broadly (beyond mTORC1 inhibition alone)

• AMPK is the mechanistic link between energy-sensing interventions (caloric restriction, exercise, metformin) and mTORC1 inhibition -- but AMPK activation is not itself equivalent to direct mTORC1 binding inhibition like rapamycin's mechanism.
• Metformin is classified in this dataset as 'mTOR-adjacent' specifically because its primary target is AMPK/mitochondrial complex I, with mTORC1 inhibition as a downstream, indirect consequence.

Source tier

Tier 2 · Biological synthesis (author-cluster reviews, not primary trial data) Reference synthesis attributed in the brief to the Saxton & Sabatini; Laplante & Sabatini; and Liu & Sabatini mTOR review literature (author-cluster attribution, tier 2, brief §4). Exact article-level PMID/DOI not supplied in the sourcing brief and is not fabricated here.