Mitochondrial respiratory chain complex I and AMP-activated protein kinase pathway (Complex I/AMPK pathway)

The Mitochondrial respiratory chain complex I and AMP-activated protein kinase (AMPK) pathway is a central metabolic axis that regulates cellular energy homeostasis [1, 5]. Mitochondrial Complex I, or NADH:ubiquinone oxidoreductase, is the largest enzyme complex in the electron transport chain and is essential for ATP production via oxidative phosphorylation [3, 9]. When Complex I is inhibited by drugs such as metformin or berberine, the resulting drop in ATP levels leads to a compensatory rise in the AMP/ATP ratio [2, 8]. This change in energy charge is sensed by AMPK, which becomes activated through allosteric binding of AMP and phosphorylation by upstream kinases like LKB1 [1, 7]. Once active, AMPK functions as a metabolic master switch, inhibiting energy-intensive processes such as hepatic gluconeogenesis and lipid synthesis while stimulating glucose uptake and fatty acid oxidation [4, 6]. This pathway is the primary therapeutic target for type 2 diabetes and is increasingly studied for its potential in treating cancer, neurodegenerative diseases, and age-related metabolic decline [5, 12].

Other names

NADH:ubiquinone oxidoreductase/AMPK axisMetformin target pathwayComplex I-mediated AMPK activationMitochondrial Complex I-AMPK signaling axis

Inhibition of mitochondrial Complex I leads to a decrease in ATP production and a subsequent increase in the AMP/ATP ratio, which allosterically activates AMPK and promotes its phosphorylation, leading to the suppression of gluconeogenesis and activation of catabolic pathways.