title: Succinate-to-fumarate ratio as a new metabolic marker to detect the presence of SDHB/D-related paraganglioma: initial experimental and ex vivo findings.
abstract: Pheochromocytomas (PHEOs) and paragangliomas (PGLs; extra-adrenal tumors) are rare neuroendocrine chromaffin cell tumors with a hereditary background in about 30%-35%. Those caused by succinate dehydrogenase subunit B (SDHB) germline mutations are associated with a high metastatic potential and ultimately higher patient mortality. Succinate dehydrogenase converts succinate to fumarate, uniquely linking the Krebs cycle and oxidative phosphorylation. SDH mutations result in the accumulation of succinate associated with various metabolic disturbances and the shift to aerobic glycolysis in tumor tissue. In the present study, we measured succinate and fumarate levels in mouse pheochromocytoma (MPC) and mouse tumor tissue (MTT) cells and in 10 apparently sporadic, 10 SDHB-, 5 SDHD-, and 2 neurofibromatosis 1-related PHEOs/PGLs and plasma samples using mass spectrometry. We found that the succinate-to-fumarate ratio was significantly higher in the SDHB- and SDHD-related PGLs than in apparently sporadic and neurofibromatosis 1-related PHEOs/PGLs (P = .0376). To further support our data, we silenced SDHB expression in MPC and MTT cells and evaluated the succinate and fumarate levels. Compared with control samples, SDHB-silenced MTT cells also showed an increase in the succinate-to-fumarate ratio (MTT cells: 2.45 vs 7.53), similar to the findings in SDHB-related PGLs. The present findings for the first time demonstrate a significantly increased succinate-to-fumarate ratio in SDHB/D-related PGLs and thus suggest this ratio may be used as a new metabolic marker for the detection of SDHB/D-related PHEOs/PGLs.
authors.affiliation: Program in Reproductive and Adult Endocrinology (N.L., P.B., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Second Department of Medicine (N.L.), Semmelweis University, Budapest, Hungary 1088; Section on Metabolic Control Analysis (R.P., R.L.V.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20852; Department of Molecular Medicine (P.B.), Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic 84505; Institute of Clinical Chemistry and Laboratory Medicine (G.E.), University Hospital Carl Gustav Carus at the TU Dresden, Dresden, Germany; Department of Medicine III (G.E.), University Hospital Carl Gustav Carus at the TU Dresden, Dresden, Germany 01307; Molecular Medicine Research Group (A.P.), Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary; and Department of Laboratory Medicine Institute (A.P.), Central Isotope Laboratory, Semmelweis University, Budapest, Hungary 1088.
authors.forename: Nikoletta
authors.initials: N
authors.lastname: Lendvai
authors.forename: Robert
authors.initials: R
authors.lastname: Pawlosky
authors.forename: Petra
authors.initials: P
authors.lastname: Bullova
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.forename: Attila
authors.initials: A
authors.lastname: Patocs
authors.forename: Richard L
authors.initials: RL
authors.lastname: Veech
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000737:chemistry; D002952:Citric Acid Cycle; D005260:Female; D005650:Fumarates / Q000737:chemistry*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D010085:Oxidative Phosphorylation; D010235:Paraganglioma / Q000378:metabolism*; D010766:Phosphorylation; D013385:Succinate Dehydrogenase / Q000235:genetics*; D019802:Succinic Acid / Q000737:chemistry*
chemical_list: D014408:Biomarkers, Tumor; D005650:Fumarates; C491545:SDHD protein, human; D019802:Succinic Acid; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase