Carney triad, SDH-deficient tumors, and Sdhb+/- mice share abnormal mitochondria
Eva Szarek1, Evan R Ball1, Alessio Imperiale2
1Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA.
Abstract:
Carney triad (CTr) describes the association of paragangliomas (PGL), pulmonary chondromas, and gastrointestinal (GI) stromal tumors (GISTs) with a variety of other lesions, including pheochromocytomas and adrenocortical tumors. The gene(s) that cause CTr remain(s) unknown. PGL and GISTs may be caused by loss-of-function mutations in succinate dehydrogenase (SDH) (a condition known as Carney-Stratakis syndrome (CSS)). Mitochondrial structure and function are abnormal in tissues that carry SDH defects, but they have not been studied in CTr. For the present study, we examined mitochondrial structure in human tumors and GI tissue (GIT) of mice with SDH deficiency. Tissues from 16 CTr tumors (n=12), those with isolated GIST (n=1), and those with CSS caused by SDHC (n=1) and SDHD (n=2) mutations were studied by electron microscopy (EM). Samples of GIT from mice with a heterozygous deletion in Sdhb (Sdhb(+) (/-), n=4) were also studied by EM. CTr patients presented with mostly epithelioid GISTs that were characterized by plump cells containing a centrally located, round nucleus and prominent nucleoli; these changes were almost identical to those seen in the GISTs of patients with SDH. In tumor cells from patients, regardless of diagnosis or tumor type, cytoplasm contained an increased number of mitochondria with a 'hypoxic' phenotype: mitochondria were devoid of cristae, exhibited structural abnormalities, and were of variable size. Occasionally, mitochondria were small and round; rarely, they were thin and elongated with tubular cristae. Many mitochondria exhibited amorphous fluffy material with membranous whorls or cystic structures. A similar mitochondrial hypoxic phenotype was seen in Sdhb(+) (/-) mice. We concluded that tissues from SDH-deficient tumors, those from mouse GIT, and those from CTr tumors shared identical abnormalities in mitochondrial structure and other features. Thus, the still-elusive CTr defect(s) is(are) likely to affect mitochondrial function, just like germline SDH-deficiency does.
