Mitochondrial respiratory chain complex I (NADH:ubiquinone oxidoreductase) (Complex I)

Mitochondrial respiratory chain complex I, also known as NADH:ubiquinone oxidoreductase, is the largest enzyme complex in the mitochondrial electron transport chain and is essential for ATP production via oxidative phosphorylation (Zhu et al., 2016, Nature). It functions by transferring electrons from NADH to ubiquinone, a process coupled with proton pumping across the inner mitochondrial membrane to establish a proton motive force. In the context of metabolic disease, Complex I is the primary molecular target of the biguanide drug metformin, which exerts a mild and specific inhibitory effect (Owen et al., 2000, Eur J Biochem). This inhibition leads to a decrease in cellular energy charge, increasing the AMP:ATP ratio and subsequently activating AMP-activated protein kinase (AMPK) (Zhou et al., 2001, J Clin Invest). The activation of AMPK, along with other energy-sensing mechanisms, results in the suppression of hepatic gluconeogenesis by downregulating key enzymes like glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (Foretz et al., 2010, J Clin Invest). Consequently, targeting Complex I serves as a critical strategy for reducing excessive hepatic glucose production in type 2 diabetes, although excessive inhibition carries the risk of lactic acidosis (Rena et al., 2017, Diabetologia).

Other names

NADH:ubiquinone oxidoreductaseNADH dehydrogenaseType I NADH dehydrogenaseComplex IMitochondrial respiratory chain complex I / hepatic gluconeogenesis pathways

Inhibition of mitochondrial respiratory chain complex I reduces ATP production, leading to an increased AMP:ATP ratio. This energy stress activates AMP-activated protein kinase (AMPK), which inhibits the expression and activity of key gluconeogenic enzymes in the liver, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), thereby reducing hepatic glucose output (Zhou et al., 2001, J Clin Invest; Foretz et al., 2010, J Clin Invest).