Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated Disorders
Mitochondria are involved in multiple aspects of neurodevelopmental processes and play a major role in the pathogenetic mechanisms leading to neuro-degenerative diseases. Fragile-X-related disorders (FXDs) are genetic conditions that occur due to the dynamic expansion of CGG repeats of the <i>...
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/6/3421 |
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| author | Martina Grandi Chiara Galber Cristina Gatto Veronica Nobile Cecilia Pucci Ida Schaldemose Nielsen Francesco Boldrin Giovanni Neri Pietro Chiurazzi Giancarlo Solaini Alessandra Baracca Valentina Giorgio Elisabetta Tabolacci |
| author_facet | Martina Grandi Chiara Galber Cristina Gatto Veronica Nobile Cecilia Pucci Ida Schaldemose Nielsen Francesco Boldrin Giovanni Neri Pietro Chiurazzi Giancarlo Solaini Alessandra Baracca Valentina Giorgio Elisabetta Tabolacci |
| author_sort | Martina Grandi |
| collection | DOAJ |
| description | Mitochondria are involved in multiple aspects of neurodevelopmental processes and play a major role in the pathogenetic mechanisms leading to neuro-degenerative diseases. Fragile-X-related disorders (FXDs) are genetic conditions that occur due to the dynamic expansion of CGG repeats of the <i>FMR1</i> gene encoding for the RNA-binding protein FMRP, particularly expressed in the brain. This gene expansion can lead to premutation (PM, 56–200 CGGs), full mutation (FM, >200 CGGs), or unmethylated FM (UFM), resulting in neurodegeneration, neurodevelopmental disorders, or no apparent intellectual disability, respectively. To investigate the mitochondrial mechanisms that are involved in the FXD patients, we analyzed mitochondrial morphology and bioenergetics in fibroblasts derived from patients. Donut-shaped mitochondrial morphology and excessive synthesis of critical mitochondrial proteins were detected in FM, PM, and UFM cells. Analysis of mitochondrial oxidative phosphorylation in situ reveals lower respiration in PM fibroblasts. Importantly, mitochondrial permeability transition-dependent apoptosis is sensitized to reactive oxygen species in FM, PM, and UFM models. This study elucidated the mitochondrial mechanisms that are involved in the FXD phenotypes, and indicated altered mitochondrial function and morphology. Importantly, a sensitization to permeability transition and apoptosis was revealed in FXD cells. Overall, our data suggest that mitochondria are novel drug targets to relieve the FXD symptoms. |
| first_indexed | 2024-04-24T18:11:16Z |
| format | Article |
| id | doaj.art-56e954da0747464390a83837ca8bf2a8 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T18:11:16Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-56e954da0747464390a83837ca8bf2a82024-03-27T13:46:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01256342110.3390/ijms25063421Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated DisordersMartina Grandi0Chiara Galber1Cristina Gatto2Veronica Nobile3Cecilia Pucci4Ida Schaldemose Nielsen5Francesco Boldrin6Giovanni Neri7Pietro Chiurazzi8Giancarlo Solaini9Alessandra Baracca10Valentina Giorgio11Elisabetta Tabolacci12Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, ItalyDepartment of Life Sciences and Public Health, Catholic University of Sacred Heart, 00168 Rome, ItalyDepartment of Life Sciences and Public Health, Catholic University of Sacred Heart, 00168 Rome, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, ItalyDepartment of Biology, University of Padova, 35121 Padova, ItalyDepartment of Life Sciences and Public Health, Catholic University of Sacred Heart, 00168 Rome, ItalyDepartment of Life Sciences and Public Health, Catholic University of Sacred Heart, 00168 Rome, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, ItalyDepartment of Life Sciences and Public Health, Catholic University of Sacred Heart, 00168 Rome, ItalyMitochondria are involved in multiple aspects of neurodevelopmental processes and play a major role in the pathogenetic mechanisms leading to neuro-degenerative diseases. Fragile-X-related disorders (FXDs) are genetic conditions that occur due to the dynamic expansion of CGG repeats of the <i>FMR1</i> gene encoding for the RNA-binding protein FMRP, particularly expressed in the brain. This gene expansion can lead to premutation (PM, 56–200 CGGs), full mutation (FM, >200 CGGs), or unmethylated FM (UFM), resulting in neurodegeneration, neurodevelopmental disorders, or no apparent intellectual disability, respectively. To investigate the mitochondrial mechanisms that are involved in the FXD patients, we analyzed mitochondrial morphology and bioenergetics in fibroblasts derived from patients. Donut-shaped mitochondrial morphology and excessive synthesis of critical mitochondrial proteins were detected in FM, PM, and UFM cells. Analysis of mitochondrial oxidative phosphorylation in situ reveals lower respiration in PM fibroblasts. Importantly, mitochondrial permeability transition-dependent apoptosis is sensitized to reactive oxygen species in FM, PM, and UFM models. This study elucidated the mitochondrial mechanisms that are involved in the FXD phenotypes, and indicated altered mitochondrial function and morphology. Importantly, a sensitization to permeability transition and apoptosis was revealed in FXD cells. Overall, our data suggest that mitochondria are novel drug targets to relieve the FXD symptoms.https://www.mdpi.com/1422-0067/25/6/3421fragile-X-related disorders (FXDs)neurodegenerationdonut-shape mitochondriaapoptosispermeability transition poreATP synthase |
| spellingShingle | Martina Grandi Chiara Galber Cristina Gatto Veronica Nobile Cecilia Pucci Ida Schaldemose Nielsen Francesco Boldrin Giovanni Neri Pietro Chiurazzi Giancarlo Solaini Alessandra Baracca Valentina Giorgio Elisabetta Tabolacci Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated Disorders International Journal of Molecular Sciences fragile-X-related disorders (FXDs) neurodegeneration donut-shape mitochondria apoptosis permeability transition pore ATP synthase |
| title | Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated Disorders |
| title_full | Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated Disorders |
| title_fullStr | Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated Disorders |
| title_full_unstemmed | Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated Disorders |
| title_short | Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated Disorders |
| title_sort | mitochondrial dysfunction causes cell death in patients affected by fragile x associated disorders |
| topic | fragile-X-related disorders (FXDs) neurodegeneration donut-shape mitochondria apoptosis permeability transition pore ATP synthase |
| url | https://www.mdpi.com/1422-0067/25/6/3421 |
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