| SDH5, also known as succinate dehydrogenase subunit 5 or SDHAF2, is a mitochondrial assembly factor crucial for the proper function of the succinate dehydrogenase (SDH) complex II, which operates in both the tricarboxylic acid cycle and the electron transport chain. Its primary role is to chaperone the covalent flavinylation of the catalytic SDHA subunit by facilitating the attachment of the FAD cofactor, a step essential for the oxidation of succinate to fumarate. SDH5 possesses a compact fold unique to the PF03937 protein family, with its first NMR structure elucidated in yeast. It displays a conserved surface interface that interacts with SDHA, involving key residues such as tyrosine seventy-one, tryptophan one hundred thirteen, and arginine sixty-eight, which are necessary for complex stability; SDH5 does not bind FAD directly in vitro but is indispensable for enabling FAD’s covalent linkage to SDHA within the cell. SDH5 is vital for SDH holoenzyme assembly: it binds immature SDHA to promote covalent bonding of FAD to a specific histidine residue, stabilizes the SDHA-B flavoprotein subcomplex, enables subsequent assembly of SDHB, SDHC, and SDHD subunits, and thereby supports mitochondrial respiration and ATP production. SDH5 integrates TCA cycle flux with oxidative phosphorylation and has been shown to suppress metastatic potential in lung cancer cells by inhibiting GSK3β and β-catenin signaling, leading to reduced epithelial-mesenchymal transition markers and invasion. Loss-of-function mutations in SDH5 destabilize SDH complexes, cause succinate accumulation, induce a pseudohypoxic state via HIF1α and reactive oxygen species, promote glycolysis and a Warburg metabolic shift, and upregulate immune evasion markers such as PD-L1 and ZEB1. SDH5 deficiency is linked to hereditary paraganglioma (PGL2), where germline mutations result in HIF stabilization and vascular tumors, often with maternal imprinting and age-dependent penetrance, and also to the suppression of lung cancer metastasis through disruption of key signaling pathways. |
