Neuronal and astrocyte dysfunction diverges from embryonic fibroblasts in the Ndufs4fky/fky mouse

Matthew J. Bird, Xiaonan W. Wijeyeratne, Jasper C Komen, Adrienne Laskowski, Michael T. Ryan, David R Thorburn, Ann E Frazier

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Synopsis Mitochondrial dysfunction causes a range of early-onset neurological diseases and contributes to neurodegenerative conditions. Themechanisms of neurological damage however are poorly understood, as accessing relevant tissue from patients is difficult, and appropriate models are limited. Hence, we assessed mitochondrial function in neurologically relevant primary cell lines from a CI (complex I) deficient Ndufs4 KO (knockout) mouse (Ndufs4fky/fky) modelling aspects of the mitochondrial disease LS (Leigh syndrome), as well as MEFs (mouse embryonic fibroblasts). Although CI structure and function were compromised in all Ndufs4fky/fky cell types, the mitochondrial membrane potential was selectively impaired in the MEFs, correlating with decreased CI-dependent ATP synthesis. In addition, increased ROS (reactive oxygen species) generation and altered sensitivity to cell death were only observed in Ndufs4fky/fky primary MEFs. In contrast, Ndufs4fky/fky primary isocortical neurons and primary isocortical astrocytes displayed only impaired ATP generation without mitochondrial membrane potential changes. Therefore the neurological dysfunction in the Ndufs4fky/fky mouse may partly originate from a more severe ATP depletion in neurons and astrocytes, even at the expense of maintaining the mitochondrial membrane potential. This may provide protection from cell death, but would ultimately compromise cell functionality in neurons and astrocytes. Furthermore, RET (reverse electron transfer) from complex II to CI appears more prominent in neurons than MEFs or astrocytes, and is attenuated in Ndufs4fky/fky cells.

Original languageEnglish
Article numbere00151
Pages (from-to)1-15
Number of pages15
JournalBioscience Reports
Issue number6
Publication statusPublished - 2014
Externally publishedYes


  • Metabolic stress
  • Mitochondrial disease
  • Mouse models
  • Neuropathology
  • Primary cells
  • Reactive oxygen species

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