title: Region-Specific Defects of Respiratory Capacities in the Ndufs4(KO) Mouse Brain.
abstract: BACKGROUND
  Lack of NDUFS4, a subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase), causes Leigh syndrome (LS), a progressive encephalomyopathy. Knocking out Ndufs4, either systemically or in brain only, elicits LS in mice. In patients as well as in KO mice distinct regions of the brain degenerate while surrounding tissue survives despite systemic complex I dysfunction. For the understanding of disease etiology and ultimately for the development of rationale treatments for LS, it appears important to uncover the mechanisms that govern focal neurodegeneration.
  
  
  RESULTS
  Here we used the Ndufs4(KO) mouse to investigate whether regional and temporal differences in respiratory capacity of the brain could be correlated with neurodegeneration. In the KO the respiratory capacity of synaptosomes from the degeneration prone regions olfactory bulb, brainstem and cerebellum was significantly decreased. The difference was measurable even before the onset of neurological symptoms. Furthermore, neither compensating nor exacerbating changes in glycolytic capacity of the synaptosomes were found. By contrast, the KO retained near normal levels of synaptosomal respiration in the degeneration-resistant/resilient "rest" of the brain. We also investigated non-synaptic mitochondria. The KO expectedly had diminished capacity for oxidative phosphorylation (state 3 respiration) with complex I dependent substrate combinations pyruvate/malate and glutamate/malate but surprisingly had normal activity with α-ketoglutarate/malate. No correlation between oxidative phosphorylation (pyruvate/malate driven state 3 respiration) and neurodegeneration was found: Notably, state 3 remained constant in the KO while in controls it tended to increase with time leading to significant differences between the genotypes in older mice in both vulnerable and resilient brain regions. Neither regional ROS damage, measured as HNE-modified protein, nor regional complex I stability, assessed by blue native gels, could explain regional neurodegeneration.
  
  
  CONCLUSIONS
  Our data suggests that locally insufficient respiration capacity of the nerve terminals may drive focal neurodegeneration.
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, United States of America.
authors.forename: Ernst-Bernhard
authors.initials: EB
authors.lastname: Kayser
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, United States of America.|Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Sedensky
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, United States of America.|Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Morgan
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000378:metabolism* / Q000473:pathology; D019069:Cell Respiration / Q000235:genetics; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics*; D015870:Gene Expression; D018698:Glutamic Acid / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism; D007888:Leigh Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008293:Malates / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009830:Olfactory Bulb / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D010085:Oxidative Phosphorylation; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology; D019289:Pyruvic Acid / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism / Q000473:pathology
chemical_list: D007656:Ketoglutaric Acids; D008293:Malates; C534449:Ndufs4 protein, mouse; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; C030298:malic acid; D019289:Pyruvic Acid; D042967:Electron Transport Complex I
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