Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells
Friedreich’s ataxia (FRDA) is a rare monogenic disease characterized by multisystem, slowly progressive degeneration. Because of the genetic defect in a non-coding region of <i>FXN</i> gene, FRDA cells exhibit severe deficit of frataxin protein levels. Hence, FRDA pathophysiology is char...
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| Format: | Article |
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/16/12687 |
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| author | Riccardo Luffarelli Luca Panarello Andrea Quatrana Francesca Tiano Silvia Fortuni Alessandra Rufini Florence Malisan Roberto Testi Ivano Condò |
| author_facet | Riccardo Luffarelli Luca Panarello Andrea Quatrana Francesca Tiano Silvia Fortuni Alessandra Rufini Florence Malisan Roberto Testi Ivano Condò |
| author_sort | Riccardo Luffarelli |
| collection | DOAJ |
| description | Friedreich’s ataxia (FRDA) is a rare monogenic disease characterized by multisystem, slowly progressive degeneration. Because of the genetic defect in a non-coding region of <i>FXN</i> gene, FRDA cells exhibit severe deficit of frataxin protein levels. Hence, FRDA pathophysiology is characterized by a plethora of metabolic disruptions related to iron metabolism, mitochondrial homeostasis and oxidative stress. Importantly, an impairment of the antioxidant defences exacerbates the oxidative damage. This appears closely associated with the disablement of key antioxidant proteins, such as the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and the mitochondrial superoxide dismutase (MnSOD). The cytokine interferon gamma (IFN-γ) has been shown to increase frataxin expression in FRDA cells and to improve functional deficits in FRDA mice. Currently, IFN-γ represents a potential therapy under clinical evaluation in FRDA patients. Here, we show that IFN-γ induces a rapid expression of Nrf2 and MnSOD in different cell types, including FRDA patient-derived fibroblasts. Our data indicate that IFN-γ signals two separate pathways to enhance Nrf2 and MnSOD levels in FRDA fibroblasts. MnSOD expression increased through an early transcriptional regulation, whereas the levels of Nrf2 are induced by a post-transcriptional mechanism. We demonstrate that the treatment of FRDA fibroblasts with IFN-γ stimulates a non-canonical Nrf2 activation pathway through p21 and potentiates antioxidant responses under exposure to hydrogen peroxide. Moreover, IFN-γ significantly reduced the sensitivity to hydrogen peroxide-induced cell death in FRDA fibroblasts. Collectively, these results indicate the presence of multiple pathways triggered by IFN-γ with therapeutic relevance to FRDA. |
| first_indexed | 2024-03-10T23:52:23Z |
| format | Article |
| id | doaj.art-6af5911f8f3a43c793988cecd58d4265 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:52:23Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6af5911f8f3a43c793988cecd58d42652023-11-19T01:27:24ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124161268710.3390/ijms241612687Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia CellsRiccardo Luffarelli0Luca Panarello1Andrea Quatrana2Francesca Tiano3Silvia Fortuni4Alessandra Rufini5Florence Malisan6Roberto Testi7Ivano Condò8Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyFriedreich’s ataxia (FRDA) is a rare monogenic disease characterized by multisystem, slowly progressive degeneration. Because of the genetic defect in a non-coding region of <i>FXN</i> gene, FRDA cells exhibit severe deficit of frataxin protein levels. Hence, FRDA pathophysiology is characterized by a plethora of metabolic disruptions related to iron metabolism, mitochondrial homeostasis and oxidative stress. Importantly, an impairment of the antioxidant defences exacerbates the oxidative damage. This appears closely associated with the disablement of key antioxidant proteins, such as the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and the mitochondrial superoxide dismutase (MnSOD). The cytokine interferon gamma (IFN-γ) has been shown to increase frataxin expression in FRDA cells and to improve functional deficits in FRDA mice. Currently, IFN-γ represents a potential therapy under clinical evaluation in FRDA patients. Here, we show that IFN-γ induces a rapid expression of Nrf2 and MnSOD in different cell types, including FRDA patient-derived fibroblasts. Our data indicate that IFN-γ signals two separate pathways to enhance Nrf2 and MnSOD levels in FRDA fibroblasts. MnSOD expression increased through an early transcriptional regulation, whereas the levels of Nrf2 are induced by a post-transcriptional mechanism. We demonstrate that the treatment of FRDA fibroblasts with IFN-γ stimulates a non-canonical Nrf2 activation pathway through p21 and potentiates antioxidant responses under exposure to hydrogen peroxide. Moreover, IFN-γ significantly reduced the sensitivity to hydrogen peroxide-induced cell death in FRDA fibroblasts. Collectively, these results indicate the presence of multiple pathways triggered by IFN-γ with therapeutic relevance to FRDA.https://www.mdpi.com/1422-0067/24/16/12687Friedreich’s ataxiainterferon gammacytoprotectionNrf2MnSOD |
| spellingShingle | Riccardo Luffarelli Luca Panarello Andrea Quatrana Francesca Tiano Silvia Fortuni Alessandra Rufini Florence Malisan Roberto Testi Ivano Condò Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells International Journal of Molecular Sciences Friedreich’s ataxia interferon gamma cytoprotection Nrf2 MnSOD |
| title | Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells |
| title_full | Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells |
| title_fullStr | Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells |
| title_full_unstemmed | Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells |
| title_short | Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells |
| title_sort | interferon gamma enhances cytoprotective pathways via nrf2 and mnsod induction in friedreich s ataxia cells |
| topic | Friedreich’s ataxia interferon gamma cytoprotection Nrf2 MnSOD |
| url | https://www.mdpi.com/1422-0067/24/16/12687 |
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