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

PLoS One. 2021 Jul 28;16(7):e0255355. doi: 10.1371/journal.pone.0255355. eCollection 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / growth & development
  • Brain / metabolism
  • Brain / pathology*
  • Cell Differentiation
  • Cells, Cultured
  • DNA, Mitochondrial / metabolism
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics*
  • 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
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / deficiency
  • Mitochondrial Proteins / genetics*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neurogenesis
  • Oxidative Stress*
  • Reactive Oxygen Species / metabolism
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*

Substances

  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Electron Transport Chain Complex Proteins
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Transcription Factors
  • mitochondrial transcription factor A

Grants and funding

This research was supported by a JMU Graduate Student Research Award (to R.K.) and the Japan Society for the Promotion of Sciences Grant-in-Aid for Scientific Research (KAKENHI) Grant 17K08497 (to K.T.) and 17K11248 and 20K07576 (to H.E.).