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Review
. 2018 Jul 10:12:466.
doi: 10.3389/fnins.2018.00466. eCollection 2018.

Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration

Moataz Abdalkader  1 , Riikka Lampinen  1 , Katja M Kanninen  1 , Tarja M Malm  1 , Jeffrey R Liddell  2
Affiliations
Review

Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration

Moataz Abdalkader et al. Front Neurosci. .

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.

Keywords: Alzheimer’s disease; Huntington’s disease; Keap1; Parkinson’s disease; RSL3; erastin; motor neuron disease; system xc-.

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Figures

FIGURE 1
FIGURE 1
Ferroptosis and its molecular regulation by Nrf2. Glutathione peroxidase 4 (Gpx4) utilizes the major cellular antioxidant glutathione (GSH) as a substrate to reduce lipid hydroperoxides (LOOH). Oxidized glutathione (GSSG) generated by Gpx4 is reduced back to glutathione by glutathione reductase (GR) in a reaction requiring NADPH, which can be regenerated by glucose-6-phosphate dehydrogenase (G6PD) and phosphogluconate dehydrogenase (PGD) of the pentose-phosphate pathway, and malic enzyme (ME). The tripeptide glutathione is synthesized by the consecutive action of glutamate-cysteine ligase (GCL) and glutathione synthetase (GSS), where the ligation of cysteine (Cys) and glutamate (Glu) by glutamate-cysteine ligase is the rate-limiting step of glutathione synthesis. The cellular import of cystine by the glutamate-cystine antiporter system xc- constitutes an significant route of cysteine supply for glutathione synthesis. Cysteine is also required for other important cellular antioxidants including thioredoxin (Trx) and thioredoxin reductase (TrxR). Ferroptosis occurs when the Gpx4-catalyzed reduction of lipid hydroperoxides is insufficient to prevent the iron-mediated generation of lipid radicals (LO∙). This leads to the propagation of lipid peroxidation and culminates in ferroptosis. Ferroptosis can be experimentally induced by inhibiting Gpx4 via the small molecule inhibitor RSL3, or by limiting glutathione supply to Gpx4. The latter is induced by direct [e.g., buthionine sulfoximine (BSO)] or indirect (e.g., by limiting cysteine availability) inhibition of glutathione synthesis. Cysteine supply is disrupted by inhibitors of system xc- including erastin, sulfasalazine, and sorafenib. Ferroptosis can also be inhibited by iron chelators such as deferoxamine and deferiprone, and lipid radical scavengers such as ferrostatin-1, liproxstatin-1, and vitamin E. Factors transcriptionally regulated by Nrf2 are indicated in blue italics, whereas factors promoting ferroptosis are indicated in red. Clearly Nrf2 signaling is likely to have an integral and pervasive impact on the manifestation of ferroptosis.
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