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

• Published in: Nature reviews. Cancer Vol. 14; no. 11; pp. 709 - 721
• Main Authors: Sabharwal, Simran S., Schumacker, Paul T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2014; Nature Publishing Group
• Subjects: 631/443/319/333/1465; 631/67/2327; Animals; Biomedicine; Cancer; Cancer Research; Care and treatment; Cell Transformation, Neoplastic; Cellular control mechanisms; DNA, Mitochondrial - genetics; Genetic aspects; Humans; Mitochondria; Mitochondria - metabolism; Mutation; Neoplasms - genetics; Neoplasms - metabolism; Oncology, Experimental; Oxidation-Reduction; Properties; Reactive oxygen species; Reactive Oxygen Species - metabolism; review-article
• ISSN: 1474-175X; 1474-1768
• DOI: 10.1038/nrc3803

Key Points 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. Mitochondria generate ROS when electrons residing on flavin groups, iron–sulphur centres or other electron transport 'way-stations' are diverted to O 2 , 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. 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. 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. 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. Oncogenes such as KRAS and MYC drive tumorigenesis in part by augmenting mitochondrial ROS generation. 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. Reactive oxygen species (ROS) are generated through various mechanisms. Accumulating evidence indicates that these moieties have important roles in promoting tumorigenesis and tumour progression; modulating the redox balance could be a strategy in targeting cancer. 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.