title: Neuronal and astrocyte dysfunction diverges from embryonic fibroblasts in the Ndufs4fky/fky mouse.
abstract: Mitochondrial dysfunction causes a range of early-onset neurological diseases and contributes to neurodegenerative conditions. The mechanisms 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.
authors.affiliation: *Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bird
authors.affiliation: ‡Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia.
authors.forename: Xiaonan W
authors.initials: XW
authors.lastname: Wijeyeratne
authors.affiliation: *Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: Jasper C
authors.initials: JC
authors.lastname: Komen
authors.affiliation: *Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Laskowski
authors.affiliation: ‡Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ryan
authors.affiliation: *Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: *Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Frazier
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics; D042963:Electron Transport Complex II / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005690:Galactose / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009336:Necrosis / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000378:metabolism; D013386:Succinates / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: C534449:Ndufs4 protein, mouse; D017382:Reactive Oxygen Species; D013386:Succinates; D012402:Rotenone; D013481:Superoxides; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I; D005690:Galactose