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.
Highlights
Reviewed by: Zezong Gu, University of Missouri, United States Maria Shadrina, Institute of Molecular Genetics (RAS), Russia Lei Liu, University of Florida, United States
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
The minimal direct evidence currently available is consistent with this and indicates that nuclear factor erythroid 2-related factor 2 (Nrf2) may be critical for protection against ferroptosis
Summary
Identifying ferroptosis in vivo is hampered by the lack of specific biomarkers. Targeting conditional knockout of Gpx to forebrain neurons of adult mice causes cognitive impairments and hippocampal degeneration reminiscent of Alzheimer’s disease (Hambright et al, 2017). These models are all accompanied by lipid peroxidation and mitochondrial impairments, consistent with ferroptosis. Oxytosis in neurons causes mitochondrial morphological changes similar to ferroptosis (Lee et al, 2011), and the toxicity of glutamate mirrors that of erastin or RSL3 in neuronal cells, and are all amenable to prevention by ferroptosis inhibitors (Liu et al, 2015; Neitemeier et al, 2017; Jelinek et al, 2018) or necrostatin-1 (Xu et al, 2007).
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