Abstract
Succinate dehydrogenase (SDH) is an enzyme complex, composed of four protein subunits, that plays a role in both the citric acid cycle and the electron transport chain. The genes for SDHA, SDHB, SDHC, and SDHD are located in the nuclear DNA, and mutations in these genes have initially been described in paragangliomas (PGL) and pheochromocytomas (PCC), which are relatively rare tumors derived from the autonomic nervous system and the adrenal medulla, respectively. Patients with SDH mutations, that are almost exclusively in the germline, are frequently affected by multiple PGL and/or PCC. In addition, other tumors have been associated with SDH mutations as well, including gastrointestinal stromal tumors, SDH-deficient renal cell carcinoma, and pituitary adenomas. Immunohistochemistry for SDHB and SDHA has been shown to be a valuable additional tool in the histopathological analysis of these tumors, and can be considered as a surrogate marker for molecular analysis. In addition, SDHB immunohistochemistry is relevant in the decision-making whether a genetic sequence variant represents a pathogenic mutation or not. In this review, we highlight the current knowledge of the physiologic and pathologic role of the SDH enzyme complex and its involvement in endocrine and non-endocrine tumors, with an emphasis on the applicability of immunohistochemistry.
Highlights
Succinate dehydrogenase (SDH) is a unique protein complex, being part of the citric acid cycle and playing a role in the mitochondrial respiratory chain
Even though other tumors than gastrointestinal stromal tumors (GIST), renal cell carcinomas (RCC), and pituitary adenomas (PA) have been reported in PCC/PGL patients with germline SDH mutations, very few of these have been proven to be related to SDH deficiency
SDHA cytoplasmic staining is negative in SDHA-mutated tumors, while tumors with mutations in any of the other SDH subunits show preserved SDHA staining (Fig. 3a–b). These findings suggest that the SDHB protein is degraded when the SDH complex is disrupted, whereas the SDHA protein remains intact [34]
Summary
Succinate dehydrogenase (SDH) is a unique protein complex, being part of the citric acid cycle and playing a role in the mitochondrial respiratory chain. Yeast mutants for SDHAF2 showed undetectable SDH activity, while the activity of other citric acid cycle enzymes and electron transport chain complexes was normal. In step 6 of the citric acid cycle, SDH catalyzes the oxidation of succinate to fumarate with the reduction of ubiquinone to ubiquinol. SDH contributes additional electrons to ubiquinone that originates from succinate [9] During these steps, an electrochemical proton gradient is created that drives the synthesis of ATP, of which huge amounts are needed in the eukaryotic cell for proper cell functioning. The functional role of the SDH complex is relevant in case of its disturbance by mutations in any of the composing proteins as will be discussed later
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