Mutant TDP-43 does not impair mitochondrial bioenergetics in vitro and in vivo
| Autor: | Giovanni Manfredi, Federica Valsecchi, Meri Gerges, Csaba Konrad, Gloria M. Palomo, Pablo M. Peixoto, Kirsten Bredvik, John Ravits, Leonard Petrucelli, Anatoly A. Starkov, Hibiki Kawamata |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
TAR DNA-binding protein 43 TDP-43 SOD1 Mutant Respiratory chain Mice Transgenic Oxidative phosphorylation Bioenergetics lcsh:Geriatrics Mitochondrion Oxidative Phosphorylation lcsh:RC346-429 Cell Line Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Mutant protein mental disorders Animals Humans Mitochondrial calcium uptake Molecular Biology lcsh:Neurology. Diseases of the nervous system ATP synthase biology Brain nutritional and metabolic diseases Molecular biology Mitochondria nervous system diseases DNA-Binding Proteins lcsh:RC952-954.6 030104 developmental biology Mutation biology.protein Calcium Neurology (clinical) ALS Energy Metabolism 030217 neurology & neurosurgery Research Article |
| Zdroj: | Molecular Neurodegeneration, Vol 12, Iss 1, Pp 1-15 (2017) Molecular Neurodegeneration |
| ISSN: | 1750-1326 |
| DOI: | 10.1186/s13024-017-0180-1 |
| Popis: | Background Mitochondrial dysfunction has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Functional studies of mitochondrial bioenergetics have focused mostly on superoxide dismutase 1 (SOD1) mutants, and showed that mutant human SOD1 impairs mitochondrial oxidative phosphorylation, calcium homeostasis, and dynamics. However, recent reports have indicated that alterations in transactivation response element DNA-binding protein 43 (TDP-43) can also lead to defects of mitochondrial morphology and dynamics. Furthermore, it was proposed that TDP-43 mutations cause oxidative phosphorylation impairment associated with respiratory chain defects and that these effects were caused by mitochondrial localization of the mutant protein. Here, we investigated the presence of bioenergetic defects in the brain of transgenic mice expressing human mutant TDP-43 (TDP-43A315T mice), patient derived fibroblasts, and human cells expressing mutant forms of TDP-43. Methods In the brain of TDP-43A315T mice, TDP-43 mutant fibroblasts, and cells expressing mutant TDP-43, we tested several bioenergetics parameters, including mitochondrial respiration, ATP synthesis, and calcium handling. Differences between mutant and control samples were evaluated by student t-test or by ANOVA, followed by Bonferroni correction, when more than two groups were compared. Mitochondrial localization of TDP-43 was investigated by immunocytochemistry in fibroblasts and by subcellular fractionation and western blot of mitochondrial fractions in mouse brain. Results We did not observe defects in any of the mitochondrial bioenergetic functions that were tested in TDP-43 mutants. We detected a small amount of TDP-43A315T peripherally associated with brain mitochondria. However, there was no correlation between TDP-43 associated with mitochondria and respiratory chain dysfunction. In addition, we observed increased calcium uptake in mitochondria from TDP-43A315T mouse brain and cells expressing A315T mutant TDP-43. Conclusions While alterations of mitochondrial morphology and dynamics in TDP-43 mutant neurons are well established, the present study did not demonstrate oxidative phosphorylation defects in TDP-43 mutants, in vitro and in vivo. On the other hand, the increase in mitochondrial calcium uptake in A315T TDP-43 mutants was an intriguing finding, which needs to be investigated further to understand its mechanisms and potential pathogenic implications. |
| Databáze: | OpenAIRE |
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