Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

Song, Xiaohua; Long, Dongyang

doi:10.3389/fnins.2020.00267

“…GPX4, so when it was replaced by sulfur in GPX4, GPX4 fails in the activity of resisting overoxidation and inhibiting ferroptosis (Ingold et al, 2018;Song and Long, 2020).…”

Section: Gpx4 and Gsh In Ferroptosismentioning

confidence: 99%

Ferroptosis, a Regulated Neuronal Cell Death Type After Intracerebral Hemorrhage

Bai

¹

,

Liu

²

,

Wang

³

2020

Front. Cell. Neurosci.

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Ferroptosis is a term that describes one form of regulated non-apoptotic cell death. It is triggered by the iron-dependent accumulation of lipid peroxides. Emerging evidence suggests a link between ferroptosis and the pathophysiological processes of neurological disorders, including stroke, degenerative diseases, neurotrauma, and cancer. Hemorrhagic stroke, also known as intracerebral hemorrhage (ICH), belongs to a devastating illness for its high level in morbidity and mortality. Currently, there are few established treatments and limited knowledge about the mechanisms of post-ICH neuronal death. The secondary brain damage after ICH is mainly attributed to oxidative stress and hemoglobin lysate, including iron, which leads to irreversible damage to neurons. Therefore, ferroptosis is becoming a common trend in research of neuronal death after ICH. Accumulative data suggest that the inhibition of ferroptosis may effectively prevent neuronal ferroptosis, thereby reducing secondary brain damage after ICH in animal models. Ferroptosis has a close relationship with oxidative damage and iron metabolism. This review reveals the pathological pathways and regulation mechanism of ferroptosis following ICH and then offers potential intervention strategies to mitigate neuron death and dysfunction after ICH.

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“…It is important to note that several of these inductions are part of the known antioxidant ferroptosis-mitigating response under the control of the transcription factor NRF2 (encoded by the Nfe2l2 gene), with experimental confirmation for FTL1 / FTH1 / HMOX1 / NQO1 [66,67]. According to GeneCards database (accessed on 31 July 2020), the NRF2 binding site exists also in the promoter of genes coding for CYB5A / CISD2 / MCEE / CREG1 / TRAF2 / ACYP1 / NSMCE2 / MAP1LC3A / GPR126 / PTGES / TRAF2 / SERPINE2, whereas STEAP4 / JMJD6 / ARMC1 / GPSM2 / MSRA promoters contain only the ARNT binding site needed by the transcription factor HIF1A to control hypoxia responses.…”

Section: Preprintsmentioning

confidence: 99%

Systematic Surveys of Iron Homeostasis Mechanisms reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence

Key

¹

,

Sen

²

,

Arsovic

³

et al. 2020

Preprint

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Iron deprivation activates mitophagy and extends lifespan in nematodes. In patients suffering from Parkinson’s disease (PD), PINK1-PRKN mutations via deficient mitophagy trigger iron accumulation and reduce lifespan. To evaluate molecular effects of iron chelator drugs as a potential PD therapy, we assessed fibroblasts by global proteome profiles and targeted transcript analyses. In mouse cells, iron shortage decreased protein abundance for iron-binding nucleotide metabolism enzymes (prominently XDH and ferritin homolog RRM2). It also decreased the expression of factors with a role for nucleotide surveillance, which associate with iron-sulfur-clusters (ISC), and are important for growth and survival. This widespread effect included prominently Nthl1-Ppat-Bdh2, but also mitochondrial Glrx5-Nfu1-Bola1, cytosolic Aco1-Abce1-Tyw5, and nuclear Dna2-Elp3-Pold1-Prim2. Incidentally, upregulated Pink1-Prkn levels explained mitophagy induction, the downregulated expression of Slc25a28 suggested it to function in iron export. The impact of PINK1 mutations in mouse and patient cells was pronounced only after iron overload, causing hyperreactive expression of ribosomal surveillance factor Abce1 and of ferritin, despite ferritin translation being repressed by IRP1. This misregulation might be explained by the deficiency of the ISC-biogenesis factor GLRX5. Our systematic survey suggests mitochondrial ISC-biogenesis and post-transcriptional iron regulation to be important in the decision, whether organisms undergo PD pathogenesis or healthy aging.

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“…It is important to note that several of these inductions are part of the known antioxidant ferroptosis-mitigating response under the control of the transcription factor NRF2 (Nuclear factor, erythroid 2 like 2, encoded by the Nfe2l2 gene), with experimental confirmation for FTL1/FTH1/HMOX1/NQO1 [NAD(P)H quinone dehydrogenase 1] [ 60 , 61 ]. According to GeneCards database (accessed on 31 July 2020), the NRF2 binding site exists also in the promoter of genes coding for CYB5A (Cytochrome B5 type A)/CISD2/MCEE (Methylmalonyl-CoA Epimerase)/CREG1 (Cellular repressor of E1A stimulated genes 1)/TRAF2 (TNF receptor-associated factor 2)/ACYP1 (Acylphosophatase 1)/NSMCE2 (Non-structural maintenance of chromosomes element 2 homolog)/MAP1LC3A (Microtubule-associated protein 1 light chain 3 alpha)/GPR126 (G-protein coupled receptor 126)/PTGES (Prostaglandin E synthase)/SERPINE2 (Serpin family E member 2), whereas STEAP4 (Six transmembrane epithelial antigen of the prostate)/JMJD6 (Jumonji domain protein 6)/ARMC1 (Armadillo repeat containing 1)/GPSM2 (G Protein signaling modulator 2)/MSRA (Methionine sulfoxide reductase A) promoters contain only the ARNT binding site (Aryl hydrocarbon receptor nuclear translocator) needed by the transcription factor HIF1A (Hypoxia-Inducible Factor 1-alpha) to control hypoxia responses.…”

Section: Resultsmentioning

confidence: 99%

Systematic Surveys of Iron Homeostasis Mechanisms Reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence

Key

¹

,

Sen

²

,

Arsovic

³

et al. 2020

Cells

View full text Add to dashboard Cite

Iron deprivation activates mitophagy and extends lifespan in nematodes. In patients suffering from Parkinson’s disease (PD), PINK1-PRKN mutations via deficient mitophagy trigger iron accumulation and reduce lifespan. To evaluate molecular effects of iron chelator drugs as a potential PD therapy, we assessed fibroblasts by global proteome profiles and targeted transcript analyses. In mouse cells, iron shortage decreased protein abundance for iron-binding nucleotide metabolism enzymes (prominently XDH and ferritin homolog RRM2). It also decreased the expression of factors with a role for nucleotide surveillance, which associate with iron-sulfur-clusters (ISC), and are important for growth and survival. This widespread effect included prominently Nthl1-Ppat-Bdh2, but also mitochondrial Glrx5-Nfu1-Bola1, cytosolic Aco1-Abce1-Tyw5, and nuclear Dna2-Elp3-Pold1-Prim2. Incidentally, upregulated Pink1-Prkn levels explained mitophagy induction, the downregulated expression of Slc25a28 suggested it to function in iron export. The impact of PINK1 mutations in mouse and patient cells was pronounced only after iron overload, causing hyperreactive expression of ribosomal surveillance factor Abce1 and of ferritin, despite ferritin translation being repressed by IRP1. This misregulation might be explained by the deficiency of the ISC-biogenesis factor GLRX5. Our systematic survey suggests mitochondrial ISC-biogenesis and post-transcriptional iron regulation to be important in the decision, whether organisms undergo PD pathogenesis or healthy aging.

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Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

Cited by 361 publications

References 178 publications

Ferroptosis, a Regulated Neuronal Cell Death Type After Intracerebral Hemorrhage

Ferroptosis, a Regulated Neuronal Cell Death Type After Intracerebral Hemorrhage

Systematic Surveys of Iron Homeostasis Mechanisms reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence

Systematic Surveys of Iron Homeostasis Mechanisms Reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence

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