Reactive oxygen species in health and disease: Finding the right balance

When oxygen takes up an electron, reactive oxygen species are formed. These free radicals can react with important molecules in our body (DNA, proteins), just like iron rusts (oxidation). Too many reactive oxygen species, called oxidative stress, result in cellular damage causing either cell death (aging) or malignant cellular transformations (carcinogenesis). Although too many reactive oxygen species are detrimental, a lower dose seems beneficial for health. We know that, but not how, epigenetic changes are induced by free radicals. Therefore, this thesis describes the relationship between oxidative stress, epigenetics and cancer. Since the mitochondria, the “cellular power plants”, are one of the main producers of intracellular free radicals, we focused on the mitochondrial reactive oxygen species and how they are used to communicate with the nucleus and the epigenetic layer of the nuclear DNA. Furthermore, we determined how the epigenetic layer of the mitochondrial DNA, a previously unappreciated regulatory layer of the mitochondrial DNA, can be modulated by these free radicals. In the end, we used the obtained knowledge to find new cures for cancer: 1. By induction of the intracellular levels of reactive oxygen species, either using a synthetic variant of the chemotherapeutic bleomycin, called N4Py, or by inhibiting Nrf2, the master regulator of oxidative stress defense responses, we could preferentially eliminate the cancer cells. 2. By reversing very locally the in cancer dysregulated epigenetic environment back to the healthy situation using a technique called “Epigenetic Editing”, we could induce cell death in cancer cells.