Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated Disorders

Author:

Grandi Martina1ORCID,Galber Chiara12,Gatto Cristina1ORCID,Nobile Veronica3,Pucci Cecilia3,Schaldemose Nielsen Ida1ORCID,Boldrin Francesco4ORCID,Neri Giovanni3,Chiurazzi Pietro35ORCID,Solaini Giancarlo1ORCID,Baracca Alessandra1ORCID,Giorgio Valentina12ORCID,Tabolacci Elisabetta3ORCID

Affiliation:

1. Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy

2. Institute of Neuroscience, Consiglio Nazionale delle Ricerche, 35121 Padova, Italy

3. Department of Life Sciences and Public Health, Catholic University of Sacred Heart, 00168 Rome, Italy

4. Department of Biology, University of Padova, 35121 Padova, Italy

5. UOC Medical Genetics, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy

Abstract

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 FMR1 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.

Funder

Fondazione Italiana per la Ricerca sul Cancro, AIRC

Ministero dell’Università e della Ricerca

Italian Association for Fragile X syndrome

Publisher

MDPI AG

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