Adenosine monophosphate-activated protein kinase–mechanistic target of rapamycin axis (AMPK–mTOR axis)

The AMPK–mTOR axis is a central signaling nexus that coordinates cellular energy status with growth and metabolic processes [4, 12]. Adenosine monophosphate-activated protein kinase (AMPK) functions as a cellular energy sensor, becoming activated during states of energy depletion (high AMP/ATP ratio) to promote catabolic pathways like fatty acid oxidation and autophagy [1, 6]. Conversely, the mechanistic target of rapamycin (mTOR), specifically the mTORC1 complex, acts as a nutrient sensor that drives anabolic processes such as protein and lipid synthesis when energy and nutrients are abundant [3, 7]. AMPK inhibits mTORC1 activity through direct phosphorylation of the Raptor subunit and indirect activation of the TSC2 complex, effectively halting cell growth under stress conditions [5, 12]. Dysregulation of this axis is a hallmark of various diseases, including type 2 diabetes, obesity, and many types of cancer, where the balance between energy sensing and growth signaling is lost [1, 6, 9]. Consequently, pharmacological modulation of the AMPK–mTOR axis using agents like metformin and rapamycin is a major area of therapeutic research for metabolic health, oncology, and longevity [2, 11].

Other names

AMPK/mTOR pathwayAMPK-mTOR signalingAMPK-mTORC1 axisAMPK-mTOR crosstalkAMPK/mTOR signaling cascade

AMPK acts as an energy sensor that, when activated by low energy levels, inhibits the mTORC1 complex both directly (via phosphorylation of Raptor) and indirectly (via activation of the TSC2 complex), thereby suppressing anabolic protein synthesis and promoting catabolic processes like autophagy to restore cellular energy balance [1, 5, 12].