Succinate dehydrogenase quinone-binding site (SDH Q-site)

The mitochondrial complex II quinone-binding site (Q-site) is a critical functional domain within the succinate dehydrogenase (SDH) complex, which uniquely participates in both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain. Located at the interface of the transmembrane subunits (SDHC and SDHD) and the iron-sulfur subunit (SDHB), the Q-site facilitates the reduction of ubiquinone to ubiquinol using electrons derived from the oxidation of succinate [1][2]. This site is a major pharmacological target for a class of fungicides known as Succinate Dehydrogenase Inhibitors (SDHIs) and is a focal point in cancer research due to the role of SDH mutations in hereditary tumor syndromes [4]. Genetic defects in the subunits forming the Q-site lead to the accumulation of succinate, which acts as an oncometabolite by inhibiting alpha-ketoglutarate-dependent dioxygenases, thereby promoting pseudohypoxia and tumorigenesis [4]. In a therapeutic context, the Q-site is studied for its potential to modulate cellular metabolism and for its role in the production of reactive oxygen species (ROS) during mitochondrial dysfunction [3].

Other names

Complex II ubiquinone-binding siteSuccinate:ubiquinone oxidoreductase Q-pocketMitochondrial complex II Q-siteSDH ubiquinone reduction site

Inhibitors bind to the Q-site pocket, which is formed by the junction of the SDHB, SDHC, and SDHD subunits, thereby blocking the transfer of electrons from the terminal iron-sulfur cluster (3Fe-4S) to ubiquinone. This prevents the reduction of ubiquinone to ubiquinol, effectively halting the electron transport chain at Complex II and often leading to the leakage of electrons and subsequent generation of superoxide radicals [2][3].