New Redox-sensitive Pathway Reveals How Cells Activate Ampk In Response To Metabolic Stress

AMP-activated macromolecule kinase (AMPK) plays a cardinal domiciled successful maintaining power equilibrium successful cells, particularly nether power stress. While upstream activation by nan kinase LKB1 is good recognized, nan precise system by which LKB1 is mobilized nether energy-deficient conditions has remained elusive.

A caller study published successful Life Metabolism reports that ROS, molecules often associated pinch oxidative stress, service arsenic captious signaling intermediates successful this process. Under conditions specified arsenic glucose deprivation aliases metformin treatment, intracellular ROS levels rise, promoting nan S-glutathionylation of PKCζ astatine cysteine 48. This post-translational modification facilitates nan relationship of PKCζ pinch nan atomic carrier macromolecule KPNA2 and its translocation into nan nucleus, wherever PKCζ phosphorylates LKB1 astatine serine 428, triggering its export to nan cytoplasm and activation of AMPK via phosphorylation of AMPK astatine Thr172. Disruption of ROS homeostasis pinch antioxidants for illustration NAC aliases vitamin E blocks this cascade, indicating nan basal domiciled of ROS successful AMPK activation.

The study besides highlights nan physiological relevance of this system in vivo. In high-fat diet-fed mice, NAC curen exacerbated hepatic lipid accumulation and blunted AMPK signaling, effects that could beryllium reversed by overexpression of a constitutively progressive shape of AMPK. Moreover, nan hypoglycemic effect of metformin was abolished by NAC successful diabetic mice, underscoring nan value of ROS successful mediating AMPK-dependent metabolic benefits.

This activity uncovers a caller redox-sensitive pathway that governs AMPK activation during power stress. It suggests that interfering pinch ROS signaling mightiness inadvertently discuss the efficacy of metabolic therapeutics for illustration metformin. The findings not only deepen our knowing of energy-sensing pathways but besides connection a model for early interventions targeting redox-AMPK signaling successful metabolic diseases.