Genotype-specific abnormalities in mitochondrial function associate with distinct profiles of energy metabolism and catecholamine content in pheochromocytoma and paraganglioma
SourceClinical Cancer Research, 19, 14, (2013), pp. 3787-3795
Article / Letter to editor
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Paediatrics - OUD tm 2017
Laboratory of Genetic, Endocrine and Metabolic Diseases
Clinical Cancer Research
SubjectDCN NN - Brain networks and neuronal communication; DCN PAC - Perception action and control; DCN PAC - Perception action and control IGMD 4: Glycostation disorders; IGMD 3: Genomic disorders and inherited multi-system disorders; IGMD 6: Hormonal regulation; IGMD 6: Hormonal regulation ONCOL 5: Aetiology, screening and detection; IGMD 8: Mitochondrial medicine; NCEBP 14: Cardiovascular diseases; ONCOL 1: Hereditary cancer and cancer-related syndromes IGMD 3: Genomic disorders and inherited multi-system disorders; ONCOL 3 - Translational research DCN MP - Plasticity and memory; ONCOL 3: Translational research IGMD 3: Genomic disorders and inherited multi-system disorders; ONCOL 1: Hereditary cancer and cancer-related syndromes IGMD 3: Genomic disorders and inherited multi-system disorders; ONCOL 3: Translational research IGMD 3: Genomic disorders and inherited multi-system disorders
PURPOSE: 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. EXPERIMENTAL DESIGN: 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.
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