Region-Specific Defects of Respiratory Capacities in the Ndufs4(KO) Mouse Brain.

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 degenerat...

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Main Authors: Ernst-Bernhard Kayser, Margaret M Sedensky, Philip G Morgan
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2016-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC4732614?pdf=render
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author Ernst-Bernhard Kayser
Margaret M Sedensky
Philip G Morgan
author_facet Ernst-Bernhard Kayser
Margaret M Sedensky
Philip G Morgan
author_sort Ernst-Bernhard Kayser
collection DOAJ
description 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.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.Our data suggests that locally insufficient respiration capacity of the nerve terminals may drive focal neurodegeneration.
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spelling doaj.art-4aa7be90d82f4bdd95a7a398a1a7e36f2022-12-21T18:47:57ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01111e014821910.1371/journal.pone.0148219Region-Specific Defects of Respiratory Capacities in the Ndufs4(KO) Mouse Brain.Ernst-Bernhard KayserMargaret M SedenskyPhilip G MorganLack 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.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.Our data suggests that locally insufficient respiration capacity of the nerve terminals may drive focal neurodegeneration.http://europepmc.org/articles/PMC4732614?pdf=render
spellingShingle Ernst-Bernhard Kayser
Margaret M Sedensky
Philip G Morgan
Region-Specific Defects of Respiratory Capacities in the Ndufs4(KO) Mouse Brain.
PLoS ONE
title Region-Specific Defects of Respiratory Capacities in the Ndufs4(KO) Mouse Brain.
title_full Region-Specific Defects of Respiratory Capacities in the Ndufs4(KO) Mouse Brain.
title_fullStr Region-Specific Defects of Respiratory Capacities in the Ndufs4(KO) Mouse Brain.
title_full_unstemmed Region-Specific Defects of Respiratory Capacities in the Ndufs4(KO) Mouse Brain.
title_short Region-Specific Defects of Respiratory Capacities in the Ndufs4(KO) Mouse Brain.
title_sort region specific defects of respiratory capacities in the ndufs4 ko mouse brain
url http://europepmc.org/articles/PMC4732614?pdf=render
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