Pharmacological NRF2 activation as a strategy for protecting mitochndrial DNA

Background
Maintaining intracellular homeostasis 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 electrophilic stress; conversely, the ability to upregulate NRF2 is compromised in many pathological conditions, and declines with aging1. Under basal conditions, NRF2 is targeted for ubiquitination and proteasomal degradation by its main cytoplasmic repressor Kelch-like ECH-associated protein 1 (KEAP1), which serves as a substrate adaptor protein for Cullin3/Rbx1 ubiquitin ligase. Electrophiles and oxidants (termed inducers) activate NRF2 by modifying cysteine sensors of KEAP1, and disrupt the cycle of KEAP1-mediated degradation of NRF22. Consequently, free KEAP1 is not regenerated, and newly synthesized NRF2 is stabilized. In the nucleus, NRF2 forms a heterodimer with a small MAF transcription factor, and the heterodimer activates transcription of target genes. NRF2 plays an important role in the control of cellular bioenergetics and mitochondrial health3.
Pharmacological activation of NRF2 protects against excess production of reactive oxygen species (ROS) by mitochondria and NADPH oxidase4, and inhibits inflammation. One mechanism involves NRF2 activation by the mitochondrial immunometabolite, itaconate, which is produced from the decarboxylation of cis-aconitate during metabolic reprogramming in activated macrophages5. From the mitochondrion, itaconate is exported to the cytoplasm where it alkylates cysteine sensors in
KEAP1 and inactivates it. Consequently, Nrf2 accumulates and inhibits the production of proinflammatory cytokines, such as IL6 and IL1B. Excess production of ROS during oxidative stress and inflammation can oxidize mitochondrial DNA (mtDNA), which then exits the mitochondrion,
triggering inflammation6. The aim of this project is to test the hypothesis that pharmacological activation of NRF2 protects mtDNA against damage and the ensuing inflammation.