Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration

Abstract

Ferroptosis is a newly described form of regulated cell death, distinct from apoptosis, necroptosis and other forms of cell death. Ferroptosis is induced by disruption of glutathione synthesis or inhibition of glutathione peroxidase 4, exacerbated by iron, and prevented by radical scavengers such as ferrostatin-1, liproxstatin-1, and endogenous vitamin E. Ferroptosis terminates with mitochondrial dysfunction and toxic lipid peroxidation. Although conclusive identification of ferroptosis in vivo is challenging, several salient and very well established features of neurodegenerative diseases are consistent with ferroptosis, including lipid peroxidation, mitochondrial disruption and iron dysregulation. Accordingly, interest in the role of ferroptosis in neurodegeneration is escalating and specific evidence is rapidly emerging. One aspect that has thus far received little attention is the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). This transcription factor regulates hundreds of genes, of which many are either directly or indirectly involved in modulating ferroptosis, including metabolism of glutathione, iron and lipids, and mitochondrial function. This potentially positions Nrf2 as a key deterministic component modulating the onset and outcomes of ferroptotic stress. The minimal direct evidence currently available is consistent with this and indicates that Nrf2 may be critical for protection against ferroptosis. In contrast, abundant evidence demonstrates that enhancing Nrf2 signaling is potently neuroprotective in models of neurodegeneration, although the exact mechanism by which this is achieved is unclear. Further studies are required to determine to extent to which the neuroprotective effects of Nrf2 activation involve the prevention of ferroptosis.

Cobalt nanoparticles trigger ferroptosis‐like cell death (oxytosis) in neuronal cells: Potential implications for neurodegenerative disease

“…Thus, Co elicits oxytosis, a ferroptosis‐like mode of cell death, in neuronal cells, with features that resemble those of neuronal cells undergoing regulated cell death in neurodegenerative diseases. It is interesting to note that several genes that are involved in ferroptosis/oxytosis, including those encoding system Xc ‐ ( SLC7A11 ) and GPX4, are transcriptionally regulated by Nrf2 . Nrf2 can also increase the expression of the multidrug resistance protein 1 (MRP1) that was shown recently to promote GSH efflux, thereby enhancing ferroptosis, which could counterbalance the protective effects of Nrf2‐dependent GSH synthesis .…”

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…NRF2 is a conserved basic leucine zipper transcription factor which affords cytoprotection against xenobiotics and ROS through induction of antioxidant and electrophile response elements (see Tebay et al, ). The beneficial roles of Nrf2‐mediated transcriptional programs in various oxidative stress‐related disease models, such as chronic neurodegeneration, inflammation, carcinogenesis, and pathogenesis associated with environmental toxicant exposure, are well recognized (see Abdalkader, Lampinen, Kanninen, Malm, & Liddell, ; Hayes, Chowdhry, Dinkova‐Kostova, & Sutherland, ). Indeed, mitochondrial ROS production is regulated by the Nrf2 pathway by controlling mitochondrial bioenergetics.…”

“…Targeting Nrf2 as a promising therapeutic avenue in neurodegeneration has been recently reviewed in the work of Abdalkader et al (), underscoring its important role in modulating neurodegenerative processes, including its ability to suppress mitochondrial dysfunction, likely underlying its crucial role in efficiently protecting and driving an anti‐stress response within the major neurogenic niches.…”

“…Accordingly, pharmacological activation of WβC-signalling by treatment with the specific GSK-3β antagonist AR can rescue the impaired NSC potential both in vitro and in vivo(L'Episcopo e al., 2013(L'Episcopo e al., , 2012 Figure 4).4.3.3 | Aging and WβC-signalling at the crossroad of Nrf2-driven Hmox1-self-adaptive response and mitochondrial dynamicsNRF2 is a conserved basic leucine zipper transcription factor which affords cytoprotection against xenobiotics and ROS through induction of antioxidant and electrophile response elements (seeTebay et al, 2015). The beneficial roles of Nrf2-mediated transcriptional programs in various oxidative stress-related disease models, such as chronic neurodegeneration, inflammation, carcinogenesis, and pathogenesis associated with environmental toxicant exposure, are well recognized (seeAbdalkader, Lampinen, Kanninen, Malm, & Liddell, 2018;Hayes, Chowdhry, Dinkova-Kostova, & Sutherland, 2015). Indeed, mitochondrial ROS production is regulated by the Nrf2 pathway by controlling mitochondrial bioenergetics.…”

A tool for browsing the Cancer Dependency Map reveals functional connections between genes and helps predict the efficacy and selectivity of candidate cancer drugs

“…S493 contains another selenoprotein TXNRD1 and its substrate TXNDC17 (Espinosa and Arnér, 2018), which are strongly correlated with four selenoprotein synthesis genes. This cluster likely represents gene that modulate ferroptosis (Abdalkader et al, 2018;Ingold et al, 2018).…”