Polydatin and Nicotinamide Prevent Iron Accumulation and Lipid Peroxidation in Cellular Models of Mitochondrial Diseases
Ferroptosis, an iron-dependent form of non-apoptotic cell death, is regulated by a complex network involving lipid metabolism, iron homeostasis, and the oxidative-reductive system, with iron accumulation and lipid peroxidation as key drivers. Mitochondrial dysfunction and ROS overproduction often un...
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2025-02-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/14/2/215 |
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| author | Paula Cilleros-Holgado David Gómez-Fernández Rocío Piñero-Pérez José Manuel Romero-Domínguez Diana Reche-López Mónica Álvarez-Córdoba Ana Romero-González Alejandra López-Cabrera Marta Castro De Oliveira Andrés Rodríguez-Sacristán Susana González-Granero José Manuel García-Verdugo José Antonio Sánchez-Alcázar |
| author_facet | Paula Cilleros-Holgado David Gómez-Fernández Rocío Piñero-Pérez José Manuel Romero-Domínguez Diana Reche-López Mónica Álvarez-Córdoba Ana Romero-González Alejandra López-Cabrera Marta Castro De Oliveira Andrés Rodríguez-Sacristán Susana González-Granero José Manuel García-Verdugo José Antonio Sánchez-Alcázar |
| author_sort | Paula Cilleros-Holgado |
| collection | DOAJ |
| description | Ferroptosis, an iron-dependent form of non-apoptotic cell death, is regulated by a complex network involving lipid metabolism, iron homeostasis, and the oxidative-reductive system, with iron accumulation and lipid peroxidation as key drivers. Mitochondrial dysfunction and ROS overproduction often underlie the pathogenesis of mitochondrial diseases, for which treatment options are limited, emphasizing the need for novel therapies. In this study, we investigated whether polydatin and nicotinamide could reverse ferroptosis-related pathological features in cellular models derived from patients with pathogenic <i>GFM1</i> variants. Mutant fibroblasts showed increased iron and lipofuscin accumulation, altered expression of iron metabolism-related proteins, elevated lipid peroxidation, and heightened susceptibility to erastin-induced ferroptosis. Treatment with polydatin and nicotinamide effectively corrected these alterations and reduced iron accumulation and lipid peroxidation in induced neurons. Furthermore, chloramphenicol treatment in control cells mimicked the mutant phenotype, suggesting that these pathological changes are linked to the mitochondrial protein synthesis defect characteristic of pathogenic <i>GFM1</i> variants. Notably, adding vitamin E to the polydatin and nicotinamide co-treatment resulted in a reduction in the minimum effective concentration, suggesting potential benefits of its inclusion. In conclusion, the combination of polydatin, nicotinamide, and vitamin E could represent a promising therapeutic option for patients with mitochondrial disorders caused by pathogenic <i>GFM1</i> variants. |
| format | Article |
| id | doaj-art-e6b305f547bf4c388bca1d1e43416a4e |
| institution | DOAJ |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
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| series | Antioxidants |
| spelling | doaj-art-e6b305f547bf4c388bca1d1e43416a4e2025-08-20T03:11:07ZengMDPI AGAntioxidants2076-39212025-02-0114221510.3390/antiox14020215Polydatin and Nicotinamide Prevent Iron Accumulation and Lipid Peroxidation in Cellular Models of Mitochondrial DiseasesPaula Cilleros-Holgado0David Gómez-Fernández1Rocío Piñero-Pérez2José Manuel Romero-Domínguez3Diana Reche-López4Mónica Álvarez-Córdoba5Ana Romero-González6Alejandra López-Cabrera7Marta Castro De Oliveira8Andrés Rodríguez-Sacristán9Susana González-Granero10José Manuel García-Verdugo11José Antonio Sánchez-Alcázar12Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, SpainCentro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, SpainCentro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, SpainCentro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, SpainCentro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, SpainCentro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, SpainCentro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, SpainCentro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, SpainNeuropediatria, Neurolinkia, C. Jardín de la Isla, 8, Local 4 y 5, 41014 Sevilla, SpainNeuropediatría, Servicio de Pediatría, Hospital Universitario Virgen Macarena, 41009 Sevilla, SpainLaboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, 46980 Valencia, SpainLaboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, 46980 Valencia, SpainCentro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, SpainFerroptosis, an iron-dependent form of non-apoptotic cell death, is regulated by a complex network involving lipid metabolism, iron homeostasis, and the oxidative-reductive system, with iron accumulation and lipid peroxidation as key drivers. Mitochondrial dysfunction and ROS overproduction often underlie the pathogenesis of mitochondrial diseases, for which treatment options are limited, emphasizing the need for novel therapies. In this study, we investigated whether polydatin and nicotinamide could reverse ferroptosis-related pathological features in cellular models derived from patients with pathogenic <i>GFM1</i> variants. Mutant fibroblasts showed increased iron and lipofuscin accumulation, altered expression of iron metabolism-related proteins, elevated lipid peroxidation, and heightened susceptibility to erastin-induced ferroptosis. Treatment with polydatin and nicotinamide effectively corrected these alterations and reduced iron accumulation and lipid peroxidation in induced neurons. Furthermore, chloramphenicol treatment in control cells mimicked the mutant phenotype, suggesting that these pathological changes are linked to the mitochondrial protein synthesis defect characteristic of pathogenic <i>GFM1</i> variants. Notably, adding vitamin E to the polydatin and nicotinamide co-treatment resulted in a reduction in the minimum effective concentration, suggesting potential benefits of its inclusion. In conclusion, the combination of polydatin, nicotinamide, and vitamin E could represent a promising therapeutic option for patients with mitochondrial disorders caused by pathogenic <i>GFM1</i> variants.https://www.mdpi.com/2076-3921/14/2/215mitochondrial diseases<i>GFM1</i>iron accumulationlipid peroxidationferroptosismtUPR |
| spellingShingle | Paula Cilleros-Holgado David Gómez-Fernández Rocío Piñero-Pérez José Manuel Romero-Domínguez Diana Reche-López Mónica Álvarez-Córdoba Ana Romero-González Alejandra López-Cabrera Marta Castro De Oliveira Andrés Rodríguez-Sacristán Susana González-Granero José Manuel García-Verdugo José Antonio Sánchez-Alcázar Polydatin and Nicotinamide Prevent Iron Accumulation and Lipid Peroxidation in Cellular Models of Mitochondrial Diseases Antioxidants mitochondrial diseases <i>GFM1</i> iron accumulation lipid peroxidation ferroptosis mtUPR |
| title | Polydatin and Nicotinamide Prevent Iron Accumulation and Lipid Peroxidation in Cellular Models of Mitochondrial Diseases |
| title_full | Polydatin and Nicotinamide Prevent Iron Accumulation and Lipid Peroxidation in Cellular Models of Mitochondrial Diseases |
| title_fullStr | Polydatin and Nicotinamide Prevent Iron Accumulation and Lipid Peroxidation in Cellular Models of Mitochondrial Diseases |
| title_full_unstemmed | Polydatin and Nicotinamide Prevent Iron Accumulation and Lipid Peroxidation in Cellular Models of Mitochondrial Diseases |
| title_short | Polydatin and Nicotinamide Prevent Iron Accumulation and Lipid Peroxidation in Cellular Models of Mitochondrial Diseases |
| title_sort | polydatin and nicotinamide prevent iron accumulation and lipid peroxidation in cellular models of mitochondrial diseases |
| topic | mitochondrial diseases <i>GFM1</i> iron accumulation lipid peroxidation ferroptosis mtUPR |
| url | https://www.mdpi.com/2076-3921/14/2/215 |
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