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

NADH:ubiquinone oxidoreductase, commonly referred to as Mitochondrial Complex I, is the largest and most complex enzyme of the mitochondrial respiratory chain, located in the inner mitochondrial membrane. It catalyzes the transfer of two electrons from NADH to ubiquinone (coenzyme Q10), coupled with the pumping of four protons from the matrix into the intermembrane space to establish the electrochemical gradient necessary for ATP synthesis (UniProt, 2023). In hepatocytes, Complex I is a major pharmacological target for the biguanide drug metformin, which is the first-line treatment for type 2 diabetes. Metformin's mild and selective inhibition of hepatic Complex I leads to a decrease in ATP production and a rise in the AMP:ATP ratio, which subsequently activates AMP-activated protein kinase (AMPK) and inhibits gluconeogenic gene expression, thereby reducing hepatic glucose output (Bridges et al., 2014; El-Mir et al., 2000). Beyond metabolic regulation, Complex I is increasingly targeted in oncology to exploit the metabolic dependencies of certain tumors, with small-molecule inhibitors like IACS-010759 designed to starve cancer cells of energy and biosynthetic precursors (Molina et al., 2018). However, therapeutic modulation of Complex I must be carefully managed, as profound inhibition can lead to severe side effects such as lactic acidosis or mitochondrial-related neurodegeneration (PubMed, 2022).

Other names

NADH dehydrogenaseNADH-coenzyme Q reductaseType I NADH dehydrogenaseMitochondrial respiratory chain complex INADH:ubiquinone oxidoreductase

Inhibition of electron transfer from NADH to ubiquinone, which reduces the mitochondrial proton gradient and ATP production, subsequently increasing the cellular AMP:ATP ratio and activating AMP-activated protein kinase (AMPK).