SDHA

SDHA, or succinate dehydrogenase complex subunit A, is a nuclear-encoded gene that produces the flavoprotein subunit of mitochondrial respiratory chain complex II, also known as succinate dehydrogenase. SDHA binds flavin adenine dinucleotide (FAD) and catalyzes the oxidation of succinate to fumarate in the tricarboxylic acid (TCA) cycle, with the electrons transferred via iron-sulfur clusters to ubiquinone in the inner mitochondrial membrane. Complex II is one of the four components of the electron transport chain and links the TCA cycle to cellular respiration.

The SDHA protein is synthesized in the cytosol and imported into mitochondria, where it assembles with other subunits, SDHB, SDHC, and SDHD, to form the functional complex II. Mutations in SDHA can disrupt complex II activity, leading to reduced cellular respiration and accumulation of metabolic intermediates such as succinate.

In humans, germline mutations in SDHA are associated with a spectrum of mitochondrial disorders and with SDH-deficient tumors, particularly paragangliomas and pheochromocytomas, and some gastrointestinal stromal tumors. Loss of SDH function can induce a pseudo-hypoxic state through stabilization of hypoxia-inducible factors, contributing to tumorigenesis.

SDHA is part of a larger set of SDHx genes (including SDHB, SDHC, SDHD) whose inactivation defines a subset of SDH-deficient tumors. Detection methods include genetic testing and immunohistochemistry for SDHB as a surrogate marker of SDH complex integrity.

See also: succinate dehydrogenase; oxidative phosphorylation; Krebs cycle; paraganglioma.