Mitochondrial Complex I (NADH:ubiquinone oxidoreductase) (Complex I)

Mitochondrial Complex I (NADH:ubiquinone oxidoreductase) is the primary molecular target of the biguanide drug metformin, which is the first-line treatment for type 2 diabetes [1, 4]. Metformin exerts its therapeutic effects by mildly and specifically inhibiting this enzyme complex, which is the first component of the mitochondrial electron transport chain [2, 11]. This inhibition leads to a reduction in mitochondrial ATP synthesis and a corresponding increase in the cellular AMP:ATP ratio, which activates the energy sensor AMP-activated protein kinase (AMPK) [3, 12]. Activation of AMPK in the liver suppresses gluconeogenesis by inhibiting key enzymes and gene expression, while in skeletal muscle, it promotes glucose uptake and fatty acid oxidation [1, 7]. Additionally, metformin has been shown to inhibit mitochondrial glycerophosphate dehydrogenase (mGPDH), further contributing to the suppression of hepatic glucose production by altering the cytosolic redox state [6, 8]. Beyond diabetes, the inhibition of Complex I by metformin is being investigated for its potential to slow aging and inhibit the growth of various cancer cells by limiting their energy supply [5, 10].

Other names

NADH dehydrogenaseNADH:ubiquinone oxidoreductaseComplex ImGPDHMitochondrial Glycerophosphate DehydrogenaseAMPKMetformin targets

Inhibition of mitochondrial complex I leads to an increase in the cellular AMP:ATP ratio, which activates AMP-activated protein kinase (AMPK), resulting in decreased hepatic gluconeogenesis and increased peripheral glucose uptake [1, 3, 11].