文章：

线粒体酶在遗传性肿瘤及其他疾病中的作用

A role for mitochondrial enzymes in inherited neoplasia and beyond

原文发布日期：2003-03-01

DOI: 10.1038/nrc1013

类型: Review Article

开放获取: 否

要点：

1. Germline heterozygous mutations in the autosomally encoded mitochondrial enzyme subunits of succinate dehydrogenase (SDH), SDHB, SDHC and SDHD, are associated with hereditary predisposition to phaeochromocytoma and paraganglioma. By contrast, homozygous germline mutations in the catalytic active-site-bearing subunit SDHA causes Leigh syndrome, which is characterized by severe neurological dysfunction and seizures.
2. Germline heterozygous mutations in another autosomally encoded mitochondrial enzyme ? fumarate hydratase (fumarase, FH) ? are associated with hereditary predisposition to papillary renal-cell carcinoma and leiomyomatosis, whereas homozygous FH mutations cause neurodegeneration.
3. SDH and FH catalyse sequential steps in the Krebs tricarboxylic-acid cycle, which generates ATP ? the cell's currency of energy. SDH is a component of complex II of the respiratory electron-transport chain.
4. The hereditary neurological diseases might be explained by complete or near-complete lack of energy generation during development, leading to free-radical formation and mitochondrial-mediated apoptotic cell death.
5. Little data exist to explain the mechanism of predisposition to cancer. Hypotheses invoke free-radical formation, leading to activation of the HIF/angiogenesis pathway and mitochondrial-mediated anti-apoptotic activity.
6. The link between mitochondrial-associated inherited neurological disease and inherited cancer might be exploited for uncovering novel functions and mechanisms for mitochondrial enzymes beyond energy production, for novel gene discovery and for clinical utility.

要点翻译：

1. 琥珀酸脱氢酶（SDH）的常染色体编码线粒体酶亚基SDHB、SDHC和SDHD的种系杂合突变与遗传性嗜铬细胞瘤和副神经节瘤易感性相关。相比之下，携带催化活性位点的亚基SDHA的纯合种系突变会导致Leigh综合征，其特征是严重的神经功能障碍和癫痫发作。
2. 另一种常染色体编码线粒体酶——富马酸水合酶（富马酸酶，FH）的种系杂合突变与遗传性乳头状肾细胞癌和平滑肌瘤病易感性相关，而纯合FH突变则导致神经退行性变。
3. SDH和FH催化三羧酸循环中的连续步骤，该循环生成ATP（细胞的能量货币）。SDH是呼吸电子传递链复合体II的组成部分。
4. 遗传性神经系统疾病可能是由于发育过程中能量生成的完全或接近完全缺乏，导致自由基形成和线粒体介导的凋亡性细胞死亡。
5. 目前几乎没有数据解释癌症易感性的机制。假设涉及自由基形成，导致HIF/血管生成通路激活和线粒体介导的抗凋亡活性。
6. 线粒体相关遗传性神经系统疾病与遗传性癌症之间的联系可用于揭示线粒体酶超越能量产生的新功能和机制，用于新基因发现和临床应用。

英文摘要：

Mitochondrial defects have been associated with neurological disorders, as well as cancers. Two ubiquitously expressed mitochondrial enzymes ? succinate dehydrogenase (SDH) and fumarate hydratase (FH, fumarase) ? catalyse sequential steps in the Krebs tricarboxylic-acid cycle. Inherited heterozygous mutations in the genes encoding these enzymes cause predispositions to two types of inherited neoplasia syndromes that do not share any component tumours. Homozygous mutations in the same genes result in severe neurological impairment. Understanding this link between inherited cancer syndromes and neurological disease could provide further insights into the mechanisms by which mitochondrial deficiencies lead to tumour development.

摘要翻译： 

线粒体缺陷与神经系统疾病以及癌症有关。两种普遍表达的线粒体酶——琥珀酸脱氢酶（SDH）和延胡索酸水合酶（FH，延胡索酸酶）——在三羧酸循环中催化连续的步骤。编码这些酶的基因发生遗传性杂合突变，会导致两种类型的遗传性肿瘤综合征，而这两种综合征并不共享任何肿瘤成分。这些基因的纯合突变则会导致严重的神经系统损害。理解这种遗传性癌症综合征与神经系统疾病之间的联系，可能有助于进一步揭示线粒体功能缺陷导致肿瘤发生的机制。

原文链接：

A role for mitochondrial enzymes in inherited neoplasia and beyond