title: Genotype-specific abnormalities in mitochondrial function associate with distinct profiles of energy metabolism and catecholamine content in pheochromocytoma and paraganglioma.
abstract: OBJECTIVE
  Pheochromocytomas and paragangliomas (PGL) are neuroendocrine tumors of sympathetic and parasympathetic paraganglia. This study investigated the relationships between genotype-specific differences in mitochondrial function and catecholamine content in PGL tumors.
  
  
  METHODS
  Respiratory chain enzyme assays and (1)H-nuclear magnetic resonance (NMR) spectroscopy at 500 MHz were conducted on homogenates of 35 sporadic PGLs and 59 PGLs from patients with hereditary mutations in succinate dehydrogenase subunits B and D (SDHB, SDHD), succinate dehydrogenase assembly factor 2, von Hippel-Lindau (VHL), rearranged during transfection (RET), neurofibromatosis type 1 (NF1), and myc-associated factor X.
  
  
  RESULTS
  In SDHx-related PGLs, a significant decrease in complex II activity (P < 0.0001) and a significant increase in complex I, III, and IV enzyme activities were observed when compared to sporadic, RET, and NF1 tumors. Also, a significant increase in citrate synthase (P < 0.0001) enzyme activity was observed in SDHx-related PGLs when compared to sporadic-, VHL-, RET-, and NF1-related tumors. An increase in succinate accumulation (P < 0.001) and decrease in ATP/ADP/AMP accumulation (P < 0.001) was observed when compared to sporadic PGLs and PGLs of other genotypes. Positive correlations (P < 0.01) were observed between respiratory chain complex II activity and total catecholamine content and ATP/ADP/AMP and total catecholamine contents in tumor tissues.
  
  
  CONCLUSIONS
  This study for the first time establishes a relationship between determinants of energy metabolism, like activity of respiratory chain enzyme complex II, ATP/ADP/AMP content, and catecholamine content in PGL tumors. Also, this study for the first time successfully uses NMR spectroscopy to detect catecholamines in PGL tumors and provides ex vivo evidence for the accumulation of succinate in PGL tumors with an SDHx mutation.
authors.affiliation: Department of Laboratory Medicine, Laboratory of Genetic Endocrine and Metabolic Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Jyotsna U
authors.initials: JU
authors.lastname: Rao
authors.forename: Udo F H
authors.initials: UF
authors.lastname: Engelke
authors.forename: Richard J T
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.forename: Nan
authors.initials: N
authors.lastname: Qin
authors.forename: Benno
authors.initials: B
authors.lastname: Kusters
authors.forename: Angelina G
authors.initials: AG
authors.lastname: Goudswaard
authors.forename: Jacques W M
authors.initials: JW
authors.lastname: Lenders
authors.forename: Ad R M M
authors.initials: AR
authors.lastname: Hermus
authors.forename: Arjen R
authors.initials: AR
authors.lastname: Mensenkamp
authors.forename: Henricus P M
authors.initials: HP
authors.lastname: Kunst
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.forename: Henri J L M
authors.initials: HJ
authors.lastname: Timmers
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D002395:Catecholamines / Q000378:metabolism*; D042963:Electron Transport Complex II / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D010235:Paraganglioma / Q000378:metabolism* / Q000473:pathology; D010673:Pheochromocytoma / Q000378:metabolism* / Q000473:pathology; D019802:Succinic Acid / Q000378:metabolism; D055815:Young Adult
chemical_list: D002395:Catecholamines; D019802:Succinic Acid; D042963:Electron Transport Complex II