Genotype-specific abnormalities in mitochondrial function associate with distinct profiles of energy metabolism and catecholamine content in pheochromocytoma and paraganglioma.

Abstract

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.

• Authors: Jyotsna U Rao, Udo F H Engelke, Richard J T Rodenburg, Ron A Wevers, Karel Pacak, Graeme Eisenhofer, Nan Qin, Benno Kusters, Angelina G Goudswaard, Jacques W M Lenders, Ad R M M Hermus, Arjen R Mensenkamp, Henricus P M Kunst, Fred C G J Sweep, Henri J L M Timmers
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 14 Pg. 3787-95 (Jul 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23723300 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Catecholamines
• Succinic Acid
• Electron Transport Complex II

Topics

• Adolescent
• Adrenal Gland Neoplasms (metabolism, pathology)
• Adult
• Catecholamines (metabolism)
• Electron Transport Complex II (metabolism)
• Energy Metabolism
• Female
• Genotype
• Humans
• Male
• Middle Aged
• Mitochondria (metabolism)
• Paraganglioma (metabolism, pathology)
• Pheochromocytoma (metabolism, pathology)
• Succinic Acid (metabolism)
• Young Adult