Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Abstract

Abstract:The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor wellknown for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

The multifaceted role of Nrf2 in mitochondrial function

“…This has since been confirmed in in vivo studies [48]. What we have been interested in establishing is a more direct involvement of Nrf2 in modulating mitochondrial function (recently reviewed in 7, ∗8, 10). We showed that respiration and ATP levels are decreased in cells and mitochondria isolated from Nrf2-knockout (Nrf2-KO) mice, while they are increased in their Keap1-knockout (Keap1-KO) and Keap1-knockdown (Keap1-KD) counterparts ∗∗49, 50.…”

“…Neurodegenerative disorders are commonly characterized by oxidative stress, mitochondrial dysfunction and protein misfolding, making them ideal targets for Nrf2 activator mediated therapy (reviewed in 10, 65, 66). Nrf2 activation has long been shown to be cytoprotective in both toxicological as well as genetic models of neurodegeneration in vitro and in vivo ∗67, 68, ∗69, ∗70, 71, ∗72, 73, 74, 75, ∗∗76.…”

“…There, it binds to antioxidant response elements (ARE) in the upstream regulatory regions of genes encoding detoxification and antioxidant enzymes, leading to their enhanced transcription 4, 5, 6. Work from our laboratories and the laboratories of other investigators, has shown that the status of Nrf2 activity affects mitochondrial function, and this has been reviewed 7, ∗8, 9, 10. The current opinion article briefly summarizes the available experimental evidence and provides an update of the most recent findings in this area.…”

Redox signaling mediated by the gut microbiota

“…Importantly, studies into Nrf2 function exposed a plethora of cellular processes other than cytoprotection which are regulated by its signaling. These include diabetes [96], cancer cell growth and chemoresistance [97][98][99], neurodegenerative diseases [100], redox homeostasis in the aging heart [101], as well as oxidative stress and inflammatory pathways [102]. Furthermore, ROS are generated as by products during inflammation in the gut epithelia, primarily due to respiratory burst activity from phagocytes described earlier in this review.…”

The role of phytochemicals in modulating intrinsic human cellular defence processes

“…620,621 The latter aspect has been harnessed in chemotherapy in which specific pharmaceuticals have been developed to inhibit Nrf2 activity in cancer cells, since it is now known that cancer cells too can take advantage of the cytoprotective properties of Nrf2 activation. 622,166 Pharmaceutical Nrf2 activation in non-cancer cases must be equally considered with caution; the failed Bardoxolone methyl trial 561 in patients with chronic kidney disease acts as stark warning that attempting to exceed normal physiological limits can have serious and sometimes fatal consequences.…”