Mitochondrial respiratory Complex II (succinate dehydrogenase) + assembly factors; SDHA/SDHB/SDHC/SDHD + SDHAF1/SDHAF2

Respiratory Complex II (succinate dehydrogenase, SDH) is the only enzyme shared between the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain. It oxidises succinate to fumarate in the matrix and feeds the released electrons into the ubiquinone pool, without pumping protons. The holoenzyme is a heterotetramer anchored in the inner membrane: the flavoprotein subunit SDHA carries a covalently bound FAD and the succinate-oxidising active site; the iron-sulfur subunit SDHB relays the electrons through three Fe-S clusters ([2Fe-2S], [4Fe-4S], [3Fe-4S]); and the two integral-membrane subunits SDHC and SDHD form the membrane anchor, bind a single heme b and provide the ubiquinone-reduction site. Two dedicated matrix assembly factors build the soluble catalytic head before it docks onto the membrane anchor: SDHAF2 (SDH5) promotes the covalent attachment of FAD to SDHA (flavinylation), and SDHAF1 — a LYR-motif protein acting with the HSC20/HSPA9 Fe-S co-chaperone system — delivers and inserts the iron-sulfur clusters into SDHB. Germline defects in the SDH subunits and assembly factors cause hereditary paraganglioma-pheochromocytoma syndromes and, when biallelic, mitochondrial complex II deficiency (Leigh syndrome, leukoencephalopathy, cardiomyopathy).