PGLs have an incidence near in the general population with approximately of cases being explained by mutations in one or more of ten PGL susceptibility genes so far described. The penetrance of familial PGL appears to be greater than depending on genotype. Some PGLs are initially benign and curable by resection. Malignancy is defined by the appearance of distant metastases, commonly to bone, liver, lung, and lymph nodes. Extra-adrenal pheochromocytomas are estimated to be malignant in cases, depending on subtype. There is currently no effective cure for malignant PGL. Remarkably, the genes whose defects predispose to PGL are not typical tumor suppressor genes. Five genes encoding subunits of the succinate dehydrogenase complex and the enzyme that flavinates SdhA are the leading tumor suppressor genes in familial PGL. Even in tumors that are apparently sporadic various SDH gene mutations were described in up to cases. Deletions at the same or closely related loci are observed in some of these cases. The remaining half of familial PGLs result from inherited mutations in von Hippel-Lindau syndrome, multiple endocrine neoplasia type 2, or neurofibromatosis genes. A broad spectrum of SDH mutations has been reported in familial PGL. Mutations in SDHB and SDHC lead to autosomal dominant inheritance of familial PGL. This pattern has recently been extended as well to SDHA. Mutations in SDHD result in imprinted paternal autosomal dominant inheritance, with new mechanistic models recently proposed. The wide range of mutations in SDH subunit genes identified in familial PGL suggests that loss of function of SDH subunits is the common cause of PGL. Our work focuses on PGL models based on disruption of the SDHB gene where mutations commonly cause extra-adrenal metastatic PGL. The succinate dehydrogenase complex is ancient and TRH Acetate highly conserved. The structure of the porcine complex has been solved by X-ray crystallography. SDH catalyzes the oxidation of succinate to fumarate in the tricarboxylic acid cycle, shuttling the extracted electrons to the ubiquinone pool of the electron transport chain. The SDH complex is composed of four small subunits situated in the inner mitochondrial membrane. Familial PGL is thus particularly remarkable because the causative genetic defects in SDH block the TCA cycle, making PGL the example par MK-7622 excellence of the Warburg effect. PGL tumor cells apparently depend only on glycolysis as an inefficient source of ATP. Aerobic glycolysis is common particularly in aggressive tumors, though the causative relationship remains unknown.
