SuccinatDehydrogenase

Succinate dehydrogenase is an essential enzyme that functions in both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain. It catalyzes the oxidation of succinate to fumarate and transfers the resulting electrons into the ubiquinone pool, linking the TCA cycle to oxidative phosphorylation.

In humans and most organisms, succinate dehydrogenase is a heterotetramer composed of four subunits: SDHA, the flavoprotein that binds FAD; SDHB, an iron-sulfur protein containing multiple Fe-S clusters; and the membrane-anchored subunits SDHC and SDHD, which coordinate ubiquinone reduction. The enzyme resides in the inner mitochondrial membrane with its catalytic portion facing the matrix.

Mechanistically, succinate oxidation by FAD in SDHA transfers electrons through the Fe-S centers of SDHB to ubiquinone, forming ubiquinol that enters the electron transport chain. Complex II contributes to respiration but does not pump protons across the membrane, unlike some other complexes in the chain.

Genetically, the enzyme is encoded by SDHA, SDHB, SDHC, and SDHD. Mutations in SDHx genes predispose individuals to hereditary tumors such as paragangliomas and pheochromocytomas, with SDHB variants often associated with higher malignancy risk. SDH deficiency leads to accumulation of succinate, an oncometabolite that inhibits α-ketoglutarate–dependent dioxygenases, promoting pseudohypoxia and epigenetic alterations that can drive tumorigenesis.

In clinical practice, loss of SDHB staining by immunohistochemistry is used as a surrogate marker for SDHx mutations in tumor diagnostics. The enzyme is highly conserved across domains of life and is present in both prokaryotes and eukaryotes, sometimes with variations in subunit composition.