文章：

癌症中的线粒体ROS：启动器、放大器还是致命弱点？

Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel?

原文发布日期：2014-10-24

DOI: 10.1038/nrc3803

类型: Review Article

开放获取: 否

要点：

1. Mitochondria contribute to the generation of ATP through oxidative phosphorylation, but they also participate in biosynthetic, metabolic and signalling functions in the cell. Some of the signalling functions are mediated by reactive oxygen species (ROS) that are generated by the electron transport chain. Alterations in mitochondrial ROS generation have been linked to a wide range of tumour cell types.
2. Mitochondria generate ROS when electrons residing on flavin groups, iron–sulphur centres or other electron transport 'way-stations' are diverted to O₂, generating superoxide. Diverse 'antioxidant enzymes' scavenge ROS and/or reverse the effects of ROS on proteins, lipids and DNA, thereby limiting the scope of oxidative damage or redox signalling.
3. Mitochondrial ROS generation can be important in cancer because it activates cellular redox signalling that drives proliferative responses and triggers activation of transcription factors that promote tumorigenesis and survival, such as hypoxia-inducible factors (HIFs). Hypoxia triggers a paradoxical increase in the release of ROS from complex III to the mitochondrial intermembrane space, facilitating signalling, cell survival and proliferation.
4. Mitochondrial DNA can be damaged by ROS, and mutant mitochondrial proteins can augment ROS generation, creating a vicious cycle that contributes to cancer initiation or progression. Mitochondrial DNA mutations have been linked to a wide range of cancer types. In some cases, mitochondrial DNA mutations regulate the tumorigenic phenotype through their effect on ROS generation.
5. Mitochondrial ROS can contribute to genomic instability, and can contribute to the activation of mitochondria-dependent cell death pathways. However, a fuller understanding of the how altered mitochondrial ROS generation contributes to cancer progression is needed.
6. Oncogenes such as KRAS and MYC drive tumorigenesis in part by augmenting mitochondrial ROS generation.
7. As many tumour cells benefit from mitochondria-derived redox signalling, a useful therapeutic approach could revolve around the inhibition of tumour-promoting mitochondrial ROS signalling without interfering with ATP production. Such an approach could limit the ability of cells to activate protective responses, leaving them vulnerable to cytotoxic agents.

要点翻译：

1. 线粒体通过氧化磷酸化参与ATP的生成，同时也在细胞中承担生物合成、代谢及信号传导功能。其中部分信号功能由电子传递链产生的活性氧（ROS）介导。线粒体ROS生成的改变与多种肿瘤细胞类型相关。
2. 当存在于黄素基团、铁硫中心或其他电子传递"中间站"的电子被转移至氧气生成超氧化物时，线粒体便会产生ROS。多种"抗氧化酶"能够清除ROS并/或逆转ROS对蛋白质、脂质和DNA的影响，从而限制氧化损伤或氧化还原信号传导的范围。
3. 线粒体ROS生成在癌症中至关重要，因为它激活驱动增殖反应的细胞氧化还原信号，并触发促进肿瘤发生和存活的转录因子（如缺氧诱导因子HIFs）的激活。缺氧会引发线粒体复合体III向膜间隙释放ROS的 paradoxical 增加，促进信号传导、细胞存活和增殖。
4. 线粒体DNA可能被ROS损伤，而突变线粒体蛋白又会增强ROS生成，形成推动癌症发生或进展的恶性循环。线粒体DNA突变与多种癌症类型相关。在某些情况下，线粒体DNA突变通过影响ROS生成来调节致瘤表型。
5. 线粒体ROS可能导致基因组不稳定性，并激活线粒体依赖性细胞死亡通路。然而，我们需要更全面地理解线粒体ROS生成改变如何促进癌症进展。
6. 诸如KRAS和MYC等癌基因通过增强线粒体ROS生成来部分驱动肿瘤发生。
7. 鉴于许多肿瘤细胞受益于线粒体来源的氧化还原信号传导，一种有效的治疗策略可能围绕抑制促瘤的线粒体ROS信号传导展开，同时不影响ATP production。这种方法可限制细胞激活保护性反应的能力，使其易受细胞毒性药物影响。

英文摘要：

Mitochondria cooperate with their host cells by contributing to bioenergetics, metabolism, biosynthesis, and cell death or survival functions. Reactive oxygen species (ROS) generated by mitochondria participate in stress signalling in normal cells but also contribute to the initiation of nuclear or mitochondrial DNA mutations that promote neoplastic transformation. In cancer cells, mitochondrial ROS amplify the tumorigenic phenotype and accelerate the accumulation of additional mutations that lead to metastatic behaviour. As mitochondria carry out important functions in normal cells, disabling their function is not a feasible therapy for cancer. However, ROS signalling contributes to proliferation and survival in many cancers, so the targeted disruption of mitochondria-to-cell redox communication represents a promising avenue for future therapy.

摘要翻译： 

线粒体通过参与生物能量代谢、生物合成以及细胞死亡或存活功能，与宿主细胞协同作用。线粒体产生的活性氧（ROS）在正常细胞中参与应激信号传导，但也会促进核DNA或线粒体DNA突变的发生，从而推动肿瘤转化。在癌细胞中，线粒体ROS会放大致瘤表型，并加速导致转移行为的额外突变的积累。由于线粒体在正常细胞中执行重要功能，因此彻底破坏其功能并非可行的癌症治疗策略。然而，ROS信号在许多癌症中促进细胞增殖与存活，因此靶向干扰线粒体与细胞之间的氧化还原通讯，代表了未来治疗的一条有前景的途径。

原文链接：

Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel?