文章：

线粒体肿瘤抑制因子：遗传和生化更新

Mitochondrial tumour suppressors: a genetic and biochemical update

原文发布日期：2005-11-01

DOI: 10.1038/nrc1737

类型: Review Article

开放获取: 否

要点：

1. Mitochondrial tumour-suppressors are nuclear-encoded mitochondrial proteins that show loss-of-function mutations in inherited or sporadic tumours. To date, four such genes are known, and they encode three of the four subunits of succinate dehydrogenase (SDHB, SDHC and SDHD) and fumarate hydratase (FH).
2. Mutations in the genes encoding SDH are predominantly linked to phaeochromocytoma or paraganglioma, whereas mutations in FH lead to leiomyoma, leiomyosarcoma and in some cases to renal cell carcinoma.
3. Both FH and SDH are enzymes of the tricarboxylic acid (TCA) cycle, whereas SDH is also a functional member of the mitochondrial respiratory chain (complex II). They are crucial elements of cellular energy metabolism, and therefore it is important to understand their role in tumour suppression.
4. The leading biological explanation for the link between loss-of-function of SDH or FH to tumorigenesis is the induction of a pseudo-hypoxic pathway. This is manifest by the induction of hypoxia-inducible factor (HIF) and its target genes under normoxic conditions.
5. Two important biochemical mechanisms that explain how mutations in mitochondrial tumour suppressor genes (particularly SDHD) contribute to tumour formation have been suggested. These mechanisms are: redox stress, resulting from increased reactive oxygen species (ROS) production in mitochondria, or metabolic signalling, involving TCA cycle metabolites as intracellular messengers.
6. Some types of mutant SDH proteins generate ROS, and these inhibit HIF prolyl hydroxylase (PHD), an enzyme that targets the α-subunit of HIF for degradation under normoxic conditions. Therefore, it was suggested that ROS can mediate pseudo-hypoxia in tumours with mutant SDH.
7. Metabolic signalling was proposed recently as an alternative, but not mutually exclusive mechanism to ROS in inducing pseudo-hypoxia — succinate levels are increased in SDH-deficient tumours and succinate can inhibit PHD, leading to HIF induction.

要点翻译：

1. 线粒体肿瘤抑制因子是核基因编码的线粒体蛋白，在遗传性或散发性肿瘤中呈现功能丧失性突变。目前已知四种此类基因，分别编码琥珀酸脱氢酶的三个亚基（SDHB、SDHC和SDHD）以及延胡索酸水合酶（FH）。
2. SDH编码基因的突变主要与嗜铬细胞瘤或副神经节瘤相关，而FH突变则导致平滑肌瘤、平滑肌肉瘤，在某些情况下还会引发肾细胞癌。
3. FH和SDH均为三羧酸循环的酶类，其中SDH同时是线粒体呼吸链（复合体II）的功能组分。它们是细胞能量代谢的关键要素，因此理解其在肿瘤抑制中的作用至关重要。
4. 关于SDH或FH功能丧失与肿瘤发生关联的主要生物学解释是假性缺氧通路的诱导。这表现为在常氧条件下缺氧诱导因子（HIF）及其靶基因的激活。
5. 目前提出两种重要生化机制解释线粒体肿瘤抑制基因（特别是SDHD）突变如何促进肿瘤形成：其一是氧化应激（由线粒体内活性氧生成增加所致），其二是代谢信号传导（涉及三羧酸循环代谢物作为细胞内信使）。
6. 某些类型的SDH突变蛋白会产生ROS，这些ROS会抑制HIF脯氨酰羟化酶（PHD）——该酶在常氧条件下靶向HIF的α亚基进行降解。因此有观点认为，在SDH突变肿瘤中ROS可能介导假性缺氧状态。
7. 近期提出的代谢信号传导机制是诱导假性缺氧的另一种（但非互斥）机制：SDH缺陷肿瘤中琥珀酸水平升高，而琥珀酸可抑制PHD，从而导致HIF激活。

英文摘要：

Since the discovery 5 years ago that the D-subunit of succinate dehydrogenase (SDHD) can behave as a classic tumour suppressor, other nuclear-encoded mitochondrial proteins (SDHB, SDHC and fumarate hydratase) have been implicated in tumour susceptibility. Mutations in these proteins are principally involved in familial predisposition to benign tumours, but the spectrum of inherited lesions is increasingly recognized to include malignant tumours, such as malignant phaeochromocytomas and renal cell carcinomas. Here we review recent advances in the field of mitochondrial tumour suppressors, the biochemical pathway that links mitochondrial dysfunction with tumorigenesis, and potential therapeutic approaches to these malignancies.

摘要翻译： 

5年前发现琥珀酸脱氢酶D亚基（SDHD）可作为经典抑癌基因后，其他由核基因编码的线粒体蛋白（SDHB、SDHC和延胡索酸水合酶）也被证实与肿瘤易感性相关。这些蛋白突变主要导致家族性良性肿瘤倾向，但越来越多的证据表明，遗传性病变的范围还包括恶性肿瘤，如恶性嗜铬细胞瘤和肾细胞癌。本文综述线粒体抑癌基因领域的最新进展、线粒体功能障碍与肿瘤发生之间的生化通路，以及针对这些恶性肿瘤的潜在治疗策略。

原文链接：

Mitochondrial tumour suppressors: a genetic and biochemical update