Succinate dehydrogenase (ubiquinone) (SDH)

Succinate dehydrogenase (SDH), also known as Mitochondrial Complex II, is a unique heterotetrameric enzyme complex that serves as a critical link between the Citric Acid Cycle (TCA cycle) and the Electron Transport Chain (ETC). It is composed of four subunits (SDHA, SDHB, SDHC, and SDHD) and is responsible for the oxidation of succinate to fumarate while simultaneously reducing ubiquinone (coenzyme Q) to ubiquinol. Unlike other complexes in the ETC, SDH does not pump protons across the mitochondrial membrane, making it a distinct metabolic checkpoint. In humans, the enzyme utilizes Coenzyme Q10, whereas the "Q6" variant typically refers to the ortholog in yeast (Saccharomyces cerevisiae). Dysfunction of the SDH complex is heavily implicated in human disease, particularly in the development of hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes and various forms of cancer, where it acts as a tumor suppressor. Mutations leading to SDH deficiency cause the accumulation of succinate, which functions as an 'oncometabolite' by inhibiting prolyl hydroxylases and inducing a pseudo-hypoxic state. While primarily a target for agricultural fungicides (SDHIs), the enzyme is a subject of intense research in oncology for the development of metabolic inhibitors or synthetic lethal strategies. Additionally, SDH is a target in the study of mitochondrial diseases like Leigh syndrome and is being explored for its role in modulating ischemia-reperfusion injury and inflammatory responses.

Other names

Succinate-ubiquinone oxidoreductaseMitochondrial Complex IISuccinate-coenzyme Q reductaseSQRSuccinate dehydrogenase complexSuccinate:ubiquinone oxidoreductase

Competitive inhibition of the succinate binding site (SDHA) or blockage of the ubiquinone binding pocket (SDHB/C/D) to disrupt electron flow and metabolic cycles.