NADH:ubiquinone oxidoreductase (Complex I) quinone-binding site (Complex I Q-site)

The mitochondrial complex I quinone-binding site is a critical functional domain within the NADH:ubiquinone oxidoreductase enzyme, which serves as the primary entry point for electrons into the respiratory chain (Hirst, 2013). This site is located at the interface of the hydrophilic peripheral arm and the hydrophobic membrane domain, primarily involving subunits NDUFS2, NDUFS7, and ND1 (Zickermann et al., 2021). Its primary biological function is to facilitate the two-electron reduction of ubiquinone to ubiquinol, a process that triggers the conformational changes necessary for the translocation of four protons across the inner mitochondrial membrane (Sazanov, 2015). This proton pumping is essential for maintaining the electrochemical gradient used by ATP synthase to produce cellular energy. The quinone-binding site is also a significant source of reactive oxygen species (ROS), which can lead to oxidative stress if the electron flow is disrupted (Brand, 2016). Clinically, mutations in the subunits forming this site are associated with mitochondrial diseases such as Leber's hereditary optic neuropathy (LHON) and Leigh syndrome (Rodenburg, 2016). Furthermore, the site is the target of various pharmacological agents, including the classic inhibitor rotenone and the anti-diabetic drug metformin, the latter of which selectively binds to the deactive (D) state of the enzyme to modulate metabolic flux (Fiedorczuk & Sazanov, 2018; Bridges et al., 2014).

Other names

NADH dehydrogenase quinone-binding siteRespiratory complex I ubiquinone-binding siteCoenzyme Q binding site of Complex IQ-chamberQuinone reduction site of Complex I

Inhibitors of the mitochondrial complex I quinone-binding site typically block the transfer of electrons from the terminal iron-sulfur cluster (N2) to the ubiquinone substrate within the Q-chamber (Hirst, 2013). This blockade prevents the reduction of ubiquinone to ubiquinol and subsequently halts the redox-driven proton pumping mechanism, leading to a decrease in the mitochondrial membrane potential and ATP production (Sazanov, 2015). Depending on the inhibitor's binding mode and the enzyme's conformational state (Active vs. Deactive), these interactions can also modulate the production of reactive oxygen species (ROS), either by promoting electron leakage at the flavin site or by stabilizing radical intermediates at the Q-site (Brand, 2016; Fiedorczuk & Sazanov, 2018).