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

The mitochondrial electron transport chain complex I ubiquinone binding site is a critical functional domain within NADH:ubiquinone oxidoreductase, the largest enzyme of the respiratory chain. This site facilitates the transfer of electrons from the terminal iron-sulfur cluster (N2) to ubiquinone (Coenzyme Q10), a process coupled with the translocation of four protons across the inner mitochondrial membrane to generate the proton motive force for ATP synthesis (Source: PubMed, PMID: 30143514). It is a complex, narrow tunnel formed by several subunits, including ND1, ND5, PSST, and TYKY (Source: UniProt). This site is a major target for various inhibitors, ranging from environmental toxins like rotenone to therapeutic agents like metformin, which mildly inhibits the site to exert metabolic effects (Source: PubMed, PMID: 24812069). Dysregulation or genetic mutations in the subunits forming this binding site are linked to severe mitochondrial disorders such as Leigh syndrome and Leber hereditary optic neuropathy (Source: NIH, GeneReviews). Furthermore, the Q-site is a significant source of superoxide production, making it a focal point for research into oxidative stress-related diseases and aging (Source: PubMed, PMID: 26119227). In oncology, targeting this site is explored to disrupt the metabolic flexibility of cancer cells (Source: PubMed, PMID: 28652331).

Other names

NADH dehydrogenase (ubiquinone) binding siteComplex I Q-binding pocketUbiquinone-binding site of Complex INADH-coenzyme Q reductase binding site

Inhibition of electron transfer from the terminal iron-sulfur cluster (N2) to ubiquinone, which prevents the reduction of ubiquinone to ubiquinol and subsequently halts the proton-pumping mechanism, leading to a decrease in the mitochondrial membrane potential and ATP production (Source: PubMed, PMID: 23313866).