ArticlePloS one2016
Region-Specific Defects of Respiratory Capacities in the Ndufs4(KO) Mouse Brain.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 39 citations in OpenAlex.
- Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.iScience · 2026Article
- Leigh Syndrome Pathomechanism Involves Region-Specific Innate Immune Activation in Ndufs4 Knockout Mice.Cellular and molecular neurobiology · 2026Article
- Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh syndrome mice.EMBO molecular medicine · 2026Article
- Chronic corticosterone administration alters synaptic mitochondrial function within the hippocampus of C57Bl/6NTac mice.Physiology & behavior · 2024Article
- Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.Redox biology · 2023Article
- Glutamine metabolism in diseases associated with mitochondrial dysfunction.Molecular and cellular neurosciences · 2023Review
- Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome.Nature metabolism · 2023Article
- Isoflurane inhibition of endocytosis is an anesthetic mechanism of action.Current biology : CB · 2022Article
- Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention.Brain : a journal of neurology · 2022Review
- Article
- Ndufs4 ablation decreases synaptophysin expression in hippocampus.Scientific reports · 2021Article
- Accessory Subunits of the Matrix Arm of Mitochondrial Complex I with a Focus on Subunit NDUFS4 and Its Role in Complex I Function and Assembly.Life (Basel, Switzerland) · 2021Review
- Metallothionein 1 Overexpression Does Not Protect Against Mitochondrial Disease Pathology in Ndufs4 Knockout Mice.Molecular neurobiology · 2021Article
- NAD+ Regeneration Rescues Lifespan, but Not Ataxia, in a Mouse Model of Brain Mitochondrial Complex I Dysfunction.Cell metabolism · 2020Article
- Novel mitochondrial and cytosolic purification pipeline for compartment-specific metabolomics in mammalian disease model tissues.Metabolomics : Official journal of the Metabolomic Society · 2020Article
- Regional metabolic signatures in the Ndufs4(KO) mouse brain implicate defective glutamate/α-ketoglutarate metabolism in mitochondrial disease.Molecular genetics and metabolism · 2020Article
- Psychological Stress Phenocopies Brain Mitochondrial Dysfunction and Motor Deficits as Observed in a Parkinsonian Rat Model.Molecular neurobiology · 2020Article
- Neurodegenerative Diseases - Is Metabolic Deficiency the Root Cause?Frontiers in neuroscience · 2020Review
- Reconstitution of the Human Nigro-striatal Pathway on-a-Chip Reveals OPA1-Dependent Mitochondrial Defects and Loss of Dopaminergic Synapses.Cell reports · 2019Article
- Leigh Syndrome Mouse Model Can Be Rescued by Interventions that Normalize Brain Hyperoxia, but Not HIF Activation.Cell metabolism · 2019Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundLack 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.
resultsHere 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.
conclusionOur data suggests that locally insufficient respiration capacity of the nerve terminals may drive focal neurodegeneration.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.