The multifaceted role of Nrf2 in mitochondrial function

The transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is the master regulator of the cellular redox homeostasis. Nrf2 target genes comprise of a large network of antioxidant enzymes, proteins involved in xenobiotic detoxification, repair and removal of damaged proteins, inhibition of inflammation, as well as other transcription factors. In recent years it has emerged that as part of its role as a regulator of cytoprotective gene expression, Nrf2 impacts mitochondrial function. Increased Nrf2 activity defends against mitochondrial toxins. Reduced glutathione, the principal small molecule antioxidant in the mammalian cell and a product of several of the downstream target genes of Nrf2, counterbalances mitochondrial ROS production. The function of Nrf2 is suppressed in mitochondria-related disorders, such as Parkinson's disease and Friedrich's ataxia. Studies using isolated mitochondria and cultured cells have demonstrated that Nrf2 deficiency leads to impaired mitochondrial fatty acid oxidation, respiration and ATP production. Small molecule activators of Nrf2 support mitochondrial integrity by promoting mitophagy and conferring resistance to oxidative stress-mediated permeability transition. Excitingly, recent studies have shown that Nrf2 also affects mitochondrial function in stem cells with implications for stem cell self-renewal, cardiomyocyte regeneration, and neural stem/progenitor cell survival.