New redox-sensitive pathway reveals how cells activate AMPK in response to metabolic stress

AMP-activated protein kinase (AMPK) plays a central role in maintaining energy balance in cells, especially under energy stress. While upstream activation by the kinase LKB1 is well recognized, the precise mechanism by which LKB1 is mobilized under energy-deficient conditions has remained elusive.

A recent study published in Life Metabolism reports that ROS, molecules often associated with oxidative stress, serve as critical signaling intermediates in this process. Under conditions such as glucose deprivation or metformin treatment, intracellular ROS levels rise, promoting the S-glutathionylation of PKCζ at cysteine 48. This post-translational modification facilitates the interaction of PKCζ with the nuclear transport protein KPNA2 and its translocation into the nucleus, where PKCζ phosphorylates LKB1 at serine 428, triggering its export to the cytoplasm and activation of AMPK via phosphorylation of AMPK at Thr172. Disruption of ROS homeostasis with antioxidants like NAC or vitamin E blocks this cascade, indicating the essential role of ROS in AMPK activation.

The study also highlights the physiological relevance of this mechanism in vivo. In high-fat diet-fed mice, NAC treatment exacerbated hepatic lipid accumulation and blunted AMPK signaling, effects that could be reversed by overexpression of a constitutively active form of AMPK. Moreover, the hypoglycemic effect of metformin was abolished by NAC in diabetic mice, underscoring the importance of ROS in mediating AMPK-dependent metabolic benefits.

This work uncovers a novel redox-sensitive pathway that governs AMPK activation during energy stress. It suggests that interfering with ROS signaling might inadvertently compromise the efficacy of metabolic therapeutics like metformin. The findings not only deepen our understanding of energy-sensing pathways but also offer a framework for future interventions targeting redox-AMPK signaling in metabolic diseases.