Departamento de Hematología, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla , Seville , Spain.
Front Oncol. 2014 Jul 30;4:200. doi: 10.3389/fonc.2014.00200. eCollection 2014.
Mitochondrial dysfunction has long been implicated in progression of cancer. As a paradigm, the "Warburg effect," which by means of a switch toward anaerobic metabolism enables cancer cells to proliferate in oxygen limiting conditions, is well established. Besides this metabolic transformation of tumors, it has been discovered that mutations in genes encoding mitochondrial proteins are the etiological factors in different types of cancer. This confers to mitochondrial dysfunction a causative role, rather than resultant, in tumor genesis beyond its role in tumor progression and development. Mitochondrial proteins encoded by tumor-suppressor genes are part of the succinate-dehydrogenase, the fumarate-hydratase, and the mitochondrial isocitrate-dehydrogenase enzymes, all of them participating in the Krebs cycle. The spectrum of tumors associated with mutations in these genes is becoming larger and varies between each enzyme. Several mechanisms of tumorigenesis have been proposed for the different enzymatic defects, most of them based on studies using cellular and animal models. Regarding the molecular pathways implicated in the oncogenic transformation, one of the first accepted theories was based on the constitutive expression of the hypoxia-inducible factor 1α (Hif1α) at normal oxygen tension, a theory referred to as "pseudo-hypoxic drive." This mechanism has been linked to the three types of mutations, thus suggesting a central role in cancer. However, other alternative molecular processes, such as oxidative stress or altered chromatin remodeling, have been also proposed to play an onco-pathogenic role. In the recent years, the role of oncometabolites, a new concept emerged from biochemical studies upon these tumors, has acquired relevance as responsible for tumor formation. Nevertheless, the actual contribution of each of these mechanisms has not been definitively established. In this review, we summarize the results obtained from mouse strains genetically modified in the three different enzymes.
线粒体功能障碍一直与癌症的进展有关。作为一个范例，“Warburg 效应”通过向无氧代谢的转变，使癌细胞能够在缺氧条件下增殖，这一效应已经得到了很好的证实。除了肿瘤的这种代谢转化，人们还发现编码线粒体蛋白的基因突变是不同类型癌症的病因。这使得线粒体功能障碍在肿瘤发生中具有因果作用，而不仅仅是在肿瘤进展和发展中的作用。肿瘤抑制基因编码的线粒体蛋白是琥珀酸脱氢酶、延胡索酸水合酶和线粒体异柠檬酸脱氢酶的一部分，它们都参与三羧酸循环。与这些基因的突变相关的肿瘤谱正在变得越来越大，并且在每种酶之间都有所不同。已经提出了几种肿瘤发生机制来解释这些酶的不同缺陷，其中大多数都是基于使用细胞和动物模型的研究。关于涉及这些基因中酶缺陷的致癌转化的分子途径，最早被接受的理论之一是在正常氧张力下组成性表达缺氧诱导因子 1α（Hif1α），这一理论被称为“伪缺氧驱动”。这种机制与三种突变类型有关，因此提示其在癌症中起核心作用。然而，其他替代的分子过程，如氧化应激或染色质重塑的改变，也被提出在致癌作用中发挥作用。近年来，从这些肿瘤的生化研究中出现的一个新概念，即致癌代谢物，作为肿瘤形成的原因，已经变得相关。然而，这些机制中的每一个的实际贡献还没有得到明确的确定。在这篇综述中，我们总结了在三种不同酶中经过基因修饰的小鼠品系获得的结果。
