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Loss of mitochondrial transcription factor A in neural stem cells leads to immature brain development and triggers the activation of the integral stress response in vivo.
- Source :
-
PloS one [PLoS One] 2021 Jul 28; Vol. 16 (7), pp. e0255355. Date of Electronic Publication: 2021 Jul 28 (Print Publication: 2021). - Publication Year :
- 2021
-
Abstract
- Mitochondrial dysfunction is significantly associated with neurological deficits and age-related neurological diseases. While mitochondria are dynamically regulated and properly maintained during neurogenesis, the manner in which mitochondrial activities are controlled and contribute to these processes is not fully understood. Mitochondrial transcription factor A (TFAM) contributes to mitochondrial function by maintaining mitochondrial DNA (mtDNA). To clarify how mitochondrial dysfunction affects neurogenesis, we induced mitochondrial dysfunction specifically in murine neural stem cells (NSCs) by inactivating Tfam. Tfam inactivation in NSCs resulted in mitochondrial dysfunction by reducing respiratory chain activities and causing a severe deficit in neural differentiation and maturation both in vivo and in vitro. Brain tissue from Tfam-deficient mice exhibited neuronal cell death primarily at layer V and microglia were activated prior to cell death. Cultured Tfam-deficient NSCs showed a reduction in reactive oxygen species produced by the mitochondria. Tfam inactivation during neurogenesis resulted in the accumulation of ATF4 and activation of target gene expression. Therefore, we propose that the integrated stress response (ISR) induced by mitochondrial dysfunction in neurogenesis is activated to protect the progression of neurodegenerative diseases.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Animals
Brain growth & development
Brain metabolism
Cell Differentiation
Cells, Cultured
DNA, Mitochondrial metabolism
DNA-Binding Proteins deficiency
Down-Regulation
Electron Transport Chain Complex Proteins genetics
Electron Transport Chain Complex Proteins metabolism
Female
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microglia cytology
Microglia metabolism
Mitochondrial Proteins deficiency
Neural Stem Cells cytology
Neural Stem Cells metabolism
Neurogenesis
Reactive Oxygen Species metabolism
Transcription Factors deficiency
Brain pathology
DNA-Binding Proteins genetics
Mitochondria metabolism
Mitochondrial Proteins genetics
Oxidative Stress
Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 16
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 34320035
- Full Text :
- https://doi.org/10.1371/journal.pone.0255355