Pharmacological NRF2 activation as a strategy for protecting mitochondrial DNA

Maintaining intracellular homeostasis and mitochondrial health in a changing environment is essential for cell survival. The nuclear factor-erythroid 2 p45-related factor 2 (NRF2, gene name NFE2L2) allows adaptation and survival under various conditions of stress. Activation of NRF2 results in upregulation of networks of proteins that protect against the consequences of proteotoxic, oxidative and inflammatory stress; conversely, the ability to upregulate NRF2 is compromised in many pathological conditions, and NRF2 is now considered a drug target.
NRF2 plays an important role in the control of cellular bioenergetics and mitochondrial health. Pharmacological activation of NRF2 protects against excess production of reactive oxygen species (ROS) by mitochondria and NADPH oxidase, and inhibits inflammation. Excess production of ROS during oxidative stress and inflammation can oxidize mitochondrial DNA (mtDNA), which then exits the mitochondrion, triggering inflammation. The overall goal of this project is to test the hypothesis that pharmacological activation of NRF2 protects mtDNA against damage and the ensuing inflammation. First, we will determine the effect of pharmacological NRF2 activation on the presence of mtDNA in the
cytosol, following challenge with pro-inflammatory stimuli (lipopolysaccharide) or redox cycling agents (paraquat or its mitochondria-targeted derivative, mito-paraquat). Second, we will employ machine learning approaches for identification and design of NRF2 activators that protect mtDNA and mitochondrial health. Third, we will characterize the mechanism by which NRF2 activation protects mtDNA.
Together, the results from this project will establish whether pharmacological activation of NRF2 is an efficient strategy for protecting mtDNA against damage, and elucidate the underlying mechanism(s). Furthermore, it may lead to identification of new compounds for subsequent development as therapeutic agents for the maintenance of mitochondrial health.