SDHD

SDHD, or succinate dehydrogenase complex subunit D, is a nuclear-encoded mitochondrial protein that forms part of the succinate dehydrogenase (Complex II) complex of the respiratory chain. It is embedded in the inner mitochondrial membrane and, together with SDHC, constitutes the membrane-anchoring portion of the complex, linking succinate oxidation in the matrix to ubiquinone reduction in the membrane.

Functionally, SDHD participates in the transfer of electrons from succinate-derived FAD-processed electrons through the complex to ubiquinone, contributing to both the citric acid cycle and the electron transport chain. In the Complex II assembly, SDHA and SDHB form the catalytic core on the matrix side, while SDHC and SDHD anchor the complex in the membrane and facilitate electron transfer to the lipid-soluble ubiquinone pool.

Genetically, the SDHD gene is expressed in many tissues, including those with paraganglionic cells. Pathogenic variants in SDHD cause hereditary paraganglioma-pheochromocytoma syndrome type 1. Tumors associated with SDHD mutations are most commonly head and neck paragangliomas; pheochromocytomas are less frequent. A notable feature of SDHD-related disease is paternal imprinting: the disease risk is higher when the pathogenic variant is inherited from the father, reflecting preferential expression of the paternal allele.

Diagnosis typically involves genetic testing for SDHD mutations, often as part of a broader SDHx gene panel that may include SDHA, SDHB, and SDHC. Management emphasizes surveillance for tumor development in at-risk individuals and appropriate treatment of identified tumors according to standard clinical guidelines. Ongoing research seeks to clarify genotype-phenotype correlations, penetrance, and therapeutic strategies for SDHD-related tumors.