Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome
| العنوان: | Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome |
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| المؤلفون: | Linlin Sun, Catarina M. Quinzii, Matthew Tracey, Elizabeth A. Jonas, Jose F. Perez-Zoghbi, Pawel Licznerski, Giulio Kleiner, Aili Wang, Richard J. Levy, Mu Yang, Lifei Wang, Guang Yang, Keren K. Griffiths |
| المصدر: | FASEB J |
| بيانات النشر: | Wiley, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Neurogenesis, Cell Respiration, Synaptogenesis, Oxidative phosphorylation, Mitochondrion, Biology, Biochemistry, Article, Fragile X Mental Retardation Protein, Mice, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Genetics, medicine, Animals, Autistic Disorder, Molecular Biology, Mice, Knockout, Thermogenesis, medicine.disease, FMR1, Mitochondria, Cell biology, Fragile X syndrome, Disease Models, Animal, 030104 developmental biology, Fragile X Syndrome, Coenzyme Q – cytochrome c reductase, Knockout mouse, Forebrain, Female, Protons, 030217 neurology & neurosurgery, Biotechnology |
| الوصف: | Fragile X syndrome (FXS) is the leading known inherited intellectual disability and the most common genetic cause of autism. The full mutation results in transcriptional silencing of the Fmr1 gene and loss of fragile X mental retardation protein (FMRP) expression. Defects in neuroenergetic capacity are known to cause a variety of neurodevelopmental disorders. Thus, we explored the integrity of forebrain mitochondria in Fmr1 knockout mice during the peak of synaptogenesis. We found inefficient thermogenic respiration due to futile proton leak in Fmr1 KO mitochondria caused by coenzyme Q (CoQ) deficiency and an open cyclosporine-sensitive channel. Repletion of mitochondrial CoQ within the Fmr1 KO forebrain closed the channel, blocked the pathological proton leak, restored rates of protein synthesis during synaptogenesis, and normalized the key phenotypic features later in life. The findings demonstrate that FMRP deficiency results in inefficient oxidative phosphorylation during the neurodevelopment and suggest that dysfunctional mitochondria may contribute to the FXS phenotype. |
| تدمد: | 1530-6860 0892-6638 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::95d16f52a57f3650872c94b59126e16cTest https://doi.org/10.1096/fj.202000283rrTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....95d16f52a57f3650872c94b59126e16c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15306860 08926638 |
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