Pollard Patrick J, Wortham Noel C, Tomlinson Ian P M
Molecular and Population Genetics Laboratory, Cancer Research UK, Lincoln's Inn Fields, London, UK.
Ann Med. 2003;35(8):632-9. doi: 10.1080/07853890310018458.
It is well documented that disturbances in mitochondrial function are associated with rare childhood disorders and possibly with many common diseases of ageing, such as Parkinson's disease and dementia. There has also been increasing evidence linking mitochondrial dysfunction with tumorigenesis. Recently, heterozygous germline mutations in two enzymes of the Krebs tricarboxylic acid cycle (TCA cycle) have been shown to predispose individuals to tumours. The two enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are ubiquitously expressed, playing a vital role in adenosine triphosphate (ATP) production through the mitochondrial respiratory chain. Germline mutations in FH are associated with leiomyomatosis and renal cell carcinoma, whilst SDH mutations are associated with predisposition to paraganglioma (PGL) and phaeochromocytoma (PCC). At present, there are few data to explain the pathway(s) involved in this predisposition to neoplasia through TCA cycle defects. We shall review the mechanisms by which mutations in FH and SDH might play a role in tumorigenesis. These include pseudo-hypoxia, mitochondrial dysfunction and impaired apoptosis, oxidative stress and anabolic drive. All of these mechanisms are currently poorly defined. To date, FH and SDH mutations have not been reported in non-familial leiomyomata, renal cancers, PCCs or PGLs. It remains entirely possible, however, that the underlying mechanisms of tumorigenesis in these sporadic tumours are the same as those in the Mendelian syndromes.
有充分的文献记载，线粒体功能紊乱与罕见的儿童疾病有关，也可能与许多常见的衰老相关疾病有关，如帕金森病和痴呆症。越来越多的证据也将线粒体功能障碍与肿瘤发生联系起来。最近，已证明三羧酸循环（TCA循环）中的两种酶的杂合种系突变会使个体易患肿瘤。这两种酶，即延胡索酸水合酶（FH）和琥珀酸脱氢酶（SDH），广泛表达，通过线粒体呼吸链在三磷酸腺苷（ATP）产生中发挥重要作用。FH的种系突变与平滑肌瘤病和肾细胞癌有关，而SDH突变与副神经节瘤（PGL）和嗜铬细胞瘤（PCC）的易感性有关。目前，几乎没有数据能解释通过TCA循环缺陷导致肿瘤易感性的相关途径。我们将综述FH和SDH突变可能在肿瘤发生中发挥作用的机制。这些机制包括假性低氧、线粒体功能障碍和凋亡受损、氧化应激和合成代谢驱动。所有这些机制目前都定义不清。迄今为止，在非家族性平滑肌瘤、肾癌、PCC或PGL中尚未报道FH和SDH突变。然而，这些散发性肿瘤的肿瘤发生潜在机制与孟德尔综合征中的机制完全相同仍是完全有可能的。
