Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome
| Autor: | 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 |
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| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | FASEB J |
| ISSN: | 1530-6860 0892-6638 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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