Mitochondrial function and content in pheochromocytoma/paraganglioma of succinate dehydrogenase mutation carriers
Mitochondrial function and content in pheochromocytoma/paraganglioma of succinate dehydrogenase mutation carriers
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DOI：
10.1530/erc-11-0263
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发表时间：
2012-06-01
影响因子：
3.9
通讯作者：
Mannelli, M.
中科院分区：
文献类型：
--
作者：
Rapizzi, E.;Ercolino, T.;Mannelli, M.
到目前为止，琥珀酸脱氢酶（SDH）损伤对整体线粒体功能的影响仍然不清楚。在这项研究中，我们评估了SDH的活性和表达和线粒体稳态在57个组织样本的嗜铬细胞瘤（PHEO）/副神经节瘤（PGL）从患者的PHEO/PGL易感基因基因分型。结果SDH活性和含量在SDH突变的肿瘤中总是降低，在两个MAX突变的患者中有一个和在四个患者中在遗传筛选时导致野生型（wt）。所有这四名野生型患者进一步筛查SDH基因、TMEM 127和MAX的大缺失，并得到野生型，但两名具有体细胞SDHD突变。MAX突变样品中的RT-PCR表明，SDH的减少取决于复合物的不稳定性，而不是SDHB表达的减少。SDH突变既不改变柠檬酸合酶（CS）的活性，也不改变电压依赖性阴离子通道（VDAC）的内容，而线粒体复合物IV（细胞色素c氧化酶（考克斯））的表达被发现在所有（突变和野生型）样本中的变化非常大，这表明在这些肿瘤中的线粒体嵴受损。总之，来自具有生殖系SDH突变的患者的肿瘤总是显示酶活性和含量降低，但SDH损伤也可能取决于SDH体细胞突变或似乎取决于MAX突变。两种野生型组织中受损的SDH活性提示其他未知易感基因的突变。最后，考克斯表达水平的极端变异性尚待解释，这强烈建议评估其他线粒体特征以更好地理解线粒体在这些肿瘤发病机制中的作用。内分泌相关癌症（2012）19 261-269
To date, the consequences of succinate dehydrogenase (SDH) impairment on overall mitochondrial functions are still obscure. In this study, we evaluated SDH activity and expression and mitochondrial homeostasis in 57 tissue samples of pheochromocytoma (PHEO)/paraganglioma (PGL) obtained from patients genotyped for PHEO/PGL susceptibility genes. The resulted SDH activity and content always decreased in SDH-mutated tumors, in one out of two MAX-mutated patients and in four patients resulted wild type (wt) at genetic screening. All these four wt patients were further screened for large deletions in SDH genes, TMEM127 and MAX and resulted wt but two had somatic SDHD mutations. The RT-PCR in the MAX-mutated sample suggests that the decrease in SDH depends on complex instability and not on a reduced SDHB expression. SDH mutations neither alter citrate synthase (CS) activity nor the content of voltage-dependent anion channel (VDAC) while the expression of the mitochondrial complex IV (cytochrome c oxidase (COX)) was found extremely variable in all (mutated and wt) samples suggesting an impairment of mitochondrial cristae in these tumors. In conclusion, tumors from patients with germ line SDH mutations invariably show decreased enzymatic activity and content, but an SDH impairment may also depend on SDH somatic mutations or, seemingly, on MAX mutations. The impaired SDH activity in the two wt tissues suggests mutations in other still unknown susceptibility genes. Finally, the extreme variability in COX expression levels is yet to be explained and this strongly suggests to evaluate other mitochondrial features to better understand the mitochondrial role in the pathogenesis of these tumors. Endocrine-Related Cancer (2012) 19 261-269