Genotype-Specific Abnormalities in Mitochondrial Function Associate with Distinct Profiles of Energy Metabolism and Catecholamine Content in Pheochromocytoma and Paraganglioma
Genotype-Specific Abnormalities in Mitochondrial Function Associate with Distinct Profiles of Energy Metabolism and Catecholamine Content in Pheochromocytoma and Paraganglioma
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DOI：
10.1158/1078-0432.ccr-12-3922
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发表时间：
2013-07-15
影响因子：
11.5
通讯作者：
Timmers, Henri J. L. M.
中科院分区：
文献类型：
--
作者：
Rao, Jyotsna U.;Engelke, Udo F. H.;Timmers, Henri J. L. M.
目的：嗜铬细胞瘤和副神经节瘤（PGL）是交感神经和副交感神经副神经节的神经内分泌肿瘤。本研究调查了 PGL 肿瘤中线粒体功能的基因型特异性差异与儿茶酚胺含量之间的关系。 实验设计：对来自琥珀酸脱氢酶亚基 B 和 D (SDHB、SDHD)、琥珀酸遗传性突变的患者的 35 份散发性 PGL 和 59 份 PGL 的匀浆进行呼吸链酶测定和 500 MHz 1 H 核磁共振 (NMR) 波谱分析。脱氢酶组装因子 2、von Hippel-Lindau (VHL)、转染期间重排 (RET)、神经纤维瘤病 1 型 (NF1) 和 myc 相关因子 X。 结果：在 SDHx 相关 PGL 中，与散发性肿瘤、RET 和 NF1 肿瘤相比，观察到复合物 II 活性显着降低 (P < 0.0001)，复合物 I、III 和 IV 酶活性显着增加。此外，与散发性、VHL、RET 和 NF1 相关肿瘤相比，SDHx 相关 PGL 中柠檬酸合酶活性显着增加 (P < 0.0001)。与零星 PGL 和其他基因型的 PGL 相比，观察到琥珀酸积累增加 (P < 0.001) 和 ATP/ADP/AMP 积累减少 (P < 0.001)。呼吸链复合物II活性与总儿茶酚胺含量以及肿瘤组织中ATP/ADP/AMP和总儿茶酚胺含量呈正相关（P < 0.01）。结论：本研究首次建立了PGL肿瘤中呼吸链酶复合物II活性、ATP/ADP/AMP含量和儿茶酚胺含量等能量代谢决定因素之间的关系。此外，本研究首次成功利用核磁共振波谱法检测PGL肿瘤中的儿茶酚胺，并为SDHx突变的PGL肿瘤中琥珀酸盐的积累提供了离体证据。 (C) 2013 年 AACR。
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. (C) 2013 AACR.