The Nrf2 induction prevents ferroptosis in Friedreich's Ataxia

Rosa, Piergiorgio La; Petrillo, Sara; Turchi, Riccardo; Berardinelli, Francesco; Schirinzi, Tommaso; Vasco, Gessica; Lettieri-Barbato, Daniele; Fiorenza, Maria Teresa; Bertini, E.; Aquilano, Katia; Piemonte, Fiorella

doi:10.1016/j.redox.2020.101791

Cited by 109 publications

(80 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Considering that the GSH-related genes are regulated by NRF2, whose expression is impaired in FRDA patients and in preclinical models of FXN deficiency ( Paupe et al, 2009 ; D’Oria et al, 2013 ; Shan et al, 2013 ; La Rosa et al, 2019 , 2020d ; Petrillo et al, 2019 ; Turchi et al, 2020b ), we evaluated if NRF2 might be differently expressed in the family. Interestingly, as reported in Figure 3 , NRF2 was not induced in the fibroblasts of the proband II-1 ( Figure 3B ) but highly stimulated in leukocytes ( Figure 3A ).…”

Section: Resultsmentioning

confidence: 99%

“…However, unlike the expected activation of the NRF2-mediated antioxidant defense, the NRF2 signaling pathway is defective in FRDA patients and in preclinical models of FXN deficiency ( Paupe et al, 2009 ; Shan et al, 2013 ; La Rosa et al, 2020a , b ), thus further exacerbating the susceptibility to oxidative stress and its induced defects in the disease ( Abeti et al, 2018 ; La Rosa et al, 2020c , d ).…”

Section: Discussionmentioning

confidence: 99%

“…It is important to note that NRF2 regulates the transcription of approximately 1% of the human genome ( Cuadrado et al, 2019 ) and that beside maintaining the cellular redox homeostasis, multiple cellular processes, including regulation of inflammation, differentiation, proliferation, cell survival, protein homeostasis, and metabolism, are among the functions influenced by its activity ( Corenblum et al, 2016 ; Robledinos-Antón et al, 2017 ; Cuadrado et al, 2019 ; Dodson et al, 2019 ; La Rosa et al, 2019 ; Turchi et al, 2020b ). Two processes were recently shown to be deeply connected to FRDA pathogenesis: (i) ferroptosis, an iron-dependent cell death caused by impaired GSH metabolism, lipid peroxidation, and mitochondrial failure ( Cotticelli et al, 2019 ; La Rosa et al, 2020d ; Turchi et al, 2020b ); and (ii) inflammation, a mechanism not yet fully understood in FRDA, but potentially involved, as demonstrated in fibroblasts of patients, where the anti-inflammatory heme-oxygenase 1 (HO-1) gene was found to be reduced ( Petrillo et al, 2019 ) and in patients who showed beneficial effects upon treatment with an NF-kB suppressor ( Lynch et al, 2019 ). Although it is undeniable that the NRF2 activation can ameliorate FRDA pathogenesis rescuing, at least in part, the detrimental effects generated by these processes, deeper and more complex regulations could be responsible for the NRF2-mediated protection observed in asymptomatic members of the family.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study

et al. 2021

Self Cite

View full text Add to dashboard Cite

Friedreich’s ataxia (FRDA) is the most frequent autosomal recessive ataxia in western countries, with a mean age of onset at 10–15 years. Patients manifest progressive cerebellar and sensory ataxia, dysarthria, lower limb pyramidal weakness, and other systemic manifestations. Previously, we described a family displaying two expanded GAA alleles not only in the proband affected by late-onset FRDA but also in the two asymptomatic family members: the mother and the younger sister. Both of them showed a significant reduction of frataxin levels, without any disease manifestation. Here, we analyzed if a protective mechanism might contribute to modulate the phenotype in this family. We particularly focused on the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), the first line of antioxidant defense in cells, and on the glutathione (GSH) system, an index of reactive oxygen species (ROS) detoxification ability. Our findings show a great reactivity of the GSH system to the frataxin deficiency, particularly in the asymptomatic mother, where the genes of GSH synthesis [glutamate–cysteine ligase (GCL)] and GSSG detoxification [GSH S-reductase (GSR)] were highly responsive. The GSR was activated even in the asymptomatic sister and in the proband, reflecting the need of buffering the GSSG increase. Furthermore, and contrasting the NRF2 expression documented in FRDA tissues, NRF2 was highly activated in the mother and in the younger sister, while it was constitutively low in the proband. This suggests that, also under frataxin depletion, the endogenous stimulation of NRF2 in asymptomatic FRDA subjects may contribute to protect against the progressive oxidative damage, helping to prevent the onset of neurological symptoms and highlighting an “out-brain origin” of the disease.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…These features may be confirmed by the results of studies on models of Friedreich’s ataxia, a disease caused by mutations in the gene encoding frataxin (the FXN gene), resulting in its decreased expression. An increase in the levels of ferroptosis markers in fibroblasts collected from patients with Friedreich’s ataxia (increased lipid peroxidation, decreased level of antioxidant enzymes, increased protein oxidation) has been reported [ 11 , 12 ]. Such studies were also performed on mouse models.…”

Section: Molecular Mechanisms Of Ferroptosismentioning

confidence: 99%

“…Such studies were also performed on mouse models. Increased levels of ferroptosis markers were observed in adipocyte precursors in FXN knock-in/knock-out (KIKO) mice (increased lipid peroxidation and decreased glutathione peroxidase 4 activity) [ 13 ], and in C2C12 mouse myoblasts after FXN gene silencing (increased expression of pro-ferroptotic and decreased expression of anti-ferroptotic genes) [ 12 , 13 ]. Moreover, fibroblasts collected from Friedreich’s ataxia patients, as well as FXN knockdown human fibrosarcoma HT-1080 cells, were considerably more sensitive to the administration of erastin, one of the best characterized ferroptosis activators [ 11 , 14 ].…”

Section: Molecular Mechanisms Of Ferroptosismentioning

confidence: 99%

Ferroptosis and Its Modulation by Autophagy in Light of the Pathogenesis of Lysosomal Storage Diseases

Pierzynowska

Rintz

Gaffke

et al. 2021

Cells

View full text Add to dashboard Cite

Ferroptosis is one of the recently described types of cell death which is dependent on many factors, including the accumulation of iron and lipid peroxidation. Its induction requires various signaling pathways. Recent discovery of ferroptosis induction pathways stimulated by autophagy, so called autophagy-dependent ferroptosis, put our attention on the role of ferroptosis in lysosomal storage diseases (LSD). Lysosome dysfunction, observed in these diseases, may influence ferroptosis efficiency, with as yet unknown consequences for the function of cells, tissues, and organisms, due to the effects of ferroptosis on physiological and pathological metabolic processes. Modulation of levels of ferrous ions and enhanced oxidative stress, which are primary markers of ferroptosis, are often described as processes associated with the pathology of LSD. Inhibition of autophagy flux and resultant accumulation of autophagosomes in neuronopathic LSD may induce autophagy-dependent ferroptosis, indicating a considerable contribution of this process in neurodegeneration. In this review article, we describe molecular mechanisms of ferroptosis in light of LSD, underlining the modulation of levels of ferroptosis markers in these diseases. Furthermore, we propose a hypothesis about the possible involvement of autophagy-dependent ferroptosis in these disorders.

show abstract

Tolterodine ameliorates inflammatory response and ferroptosis against LPS in human bladder epithelial cells

Wang,

Ji,

Jiang

et al. 2023

J Biochem & Molecular Tox

View full text Add to dashboard Cite

Bacterial endotoxin lipopolysaccharide (LPS)‐induced inflammatory response and ferroptosis play an important role in urinary tract infections. Tolterodine has been used as a urinary tract antispasmodic and anticholinergic agent. However, the effects of Tolterodine against LPS‐induced insults in human bladder epithelial cells (hBECs) have not been reported before. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide and lactate dehydrogenase release assays to determine the cell viability, reactive oxygen species (ROS) and malondialdehyde level detection were used to determine the level of oxidative stress, enzyme‐linked immunosorbent assay and Western blot analysis were used to detect the protein level. In the current study, we found that Tolterodine ameliorated LPS‐induced production of ROS and lipid oxidation in hBECs. Interestingly, Tolterodine inhibited the production of interleukin 6, interleukin‐1β, and tumor necrosis factor α. Also, Tolterodine reduced the levels of Fe2+ and suppressed ferroptosis by reducing the levels of glutathione peroxidase 4, prostaglandin‐endoperoxide synthase 2, and acyl‐CoA synthetase long‐chain family member 4 in LPS‐challenged bladder epithelial cells. Mechanistically, it was shown that Tolterodine restored the nuclear factor E2‐related factor 2 (Nrf2)/nuclear factor‐κB signaling. Importantly, inhibition of Nrf2 with its specific inhibitor ML385 abolished the protective effects of Tolterodine in the inflammatory response and ferroptosis, suggesting that the effects of Tolterodine are mediated by Nrf2. Based on these findings, we conclude that Tolterodine might serve as a promising agent for the treatment of LPS‐induced bladder inflammation.

show abstract

The Nrf2 induction prevents ferroptosis in Friedreich's Ataxia

Cited by 109 publications

References 69 publications

Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study

Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study

Ferroptosis and Its Modulation by Autophagy in Light of the Pathogenesis of Lysosomal Storage Diseases

Tolterodine ameliorates inflammatory response and ferroptosis against LPS in human bladder epithelial cells

Contact Info

Product

Resources

About