Department of Medical and Surgical Sciences, Unit of Medical Genetics, University of Bologna Medical School, 40138 Bologna, Italy.
Cold Spring Harb Perspect Biol. 2013 Feb 1;5(2):a011411. doi: 10.1101/cshperspect.a011411.
Cancer cells are characterized in general by a decrease of mitochondrial respiration and oxidative phosphorylation, together with a strong enhancement of glycolysis, the so-called Warburg effect. The decrease of mitochondrial activity in cancer cells may have multiple reasons, related either to the input of reducing equivalents to the electron transfer chain or to direct alterations of the mitochondrial respiratory complexes. In some cases, the depression of respiratory activity is clearly the consequence of disruptive mitochondrial DNA (mtDNA) mutations and leads as a consequence to enhanced generation of reactive oxygen species (ROS). By acting both as mutagens and cellular mitogens, ROS may contribute directly to cancer progression. On the basis of our experimental evidence, we suggest a deep implication of the supercomplex organization of the respiratory chain as a missing link between oxidative stress, energy failure, and tumorigenesis. We speculate that under conditions of oxidative stress, a dissociation of mitochondrial supercomplexes occurs, with destabilization of complex I and secondary enhanced generation of ROS, thus leading to a vicious circle amplifying mitochondrial dysfunction. An excellent model to dissect the role of pathogenic, disassembling mtDNA mutations in tumor progression and their contribution to the metabolic reprogramming of cancer cells (glycolysis vs. respiration) is provided by an often underdiagnosed subset of tumors, namely, the oncocytomas, characterized by disruptive mutations of mtDNA, especially of complex I subunits. Such mutations almost completely abolish complex I activity, which slows down the Krebs cycle, favoring a high ratio of α-ketoglutarate/succinate and consequent destabilization of hypoxia inducible factor 1α (HIF1α). On the other hand, if complex I is partially defective, the levels of NAD(+) may be sufficient to implement the Krebs cycle with higher levels of intermediates that stabilize HIF1α, thus favoring tumor malignancy. The threshold model we propose, based on the population-like dynamics of mitochondrial genetics (heteroplasmy vs. homoplasmy), implies that below threshold complex I is present and functioning correctly, thus favoring tumor growth, whereas above threshold, when complex I is not assembled, tumor growth is arrested. We have therefore termed "oncojanus" the mtDNA genes whose disruptive mutations have such a double-edged effect.
癌细胞的特征一般是线粒体呼吸和氧化磷酸化减少，同时糖酵解增强，即所谓的瓦伯格效应。癌细胞中线粒体活性的降低可能有多种原因，既与电子传递链的还原当量输入有关，也与线粒体呼吸复合物的直接改变有关。在某些情况下，呼吸活性的降低显然是由于线粒体 DNA（mtDNA）突变的破坏所致，因此导致活性氧（ROS）的产生增加。ROS 既作为诱变剂又作为细胞有丝分裂原，可能直接促进癌症的进展。基于我们的实验证据，我们提出了呼吸链超级复合物组织的深度影响，作为氧化应激、能量衰竭和肿瘤发生之间缺失的联系。我们推测，在氧化应激条件下，线粒体超级复合物会发生解离，导致复合物 I 的不稳定性和 ROS 的继发性增强产生，从而导致放大线粒体功能障碍的恶性循环。一种极好的模型，可以剖析致病的、破坏 mtDNA 突变在肿瘤进展中的作用及其对癌细胞代谢重编程（糖酵解与呼吸）的贡献，是一组经常被低估的肿瘤亚组，即嗜铬细胞瘤，其特征是 mtDNA 的破坏突变，特别是复合物 I 亚基。这种突变几乎完全消除了复合物 I 的活性，从而减缓了三羧酸循环，有利于α-酮戊二酸/琥珀酸的高比例，并导致缺氧诱导因子 1α（HIF1α）的不稳定性。另一方面，如果复合物 I 部分缺陷，NAD（+）的水平可能足以通过中间产物的更高水平来实施三羧酸循环，从而稳定 HIF1α，从而有利于肿瘤恶性。我们提出的基于线粒体遗传学（异质性与同质性）的群体动力学的阈值模型，意味着在阈值以下复合物 I 存在且功能正常，从而有利于肿瘤生长，而在阈值以上，当复合物 I 不组装时，肿瘤生长就会停止。因此，我们将具有这种双刃剑效应的 mtDNA 基因称为“oncjanus”。
