ArticleThe Journal of biological chemistry2012
Proteomic and metabolomic analyses of mitochondrial complex I-deficient mouse model generated by spontaneous B2 short interspersed nuclear element (SINE) insertion into NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) gene.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 65 citations in OpenAlex.
- Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity.The Journal of clinical investigation · 2021Trial
- Mitochondrial complex I deficiency-associated diseases and models.Cellular and molecular life sciences : CMLS · 2026Review
- Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.Redox biology · 2026Article
- Dysfunctional Electron Transport Chain Assembly in COXPD8.Journal of cardiovascular development and disease · 2025Article
- Tissue-Specific Regulation of Fatty Acid Metabolism in a Mouse Model of Isolated Complex I Deficiency.Proteomics · 2025Article
- Disease models of Leigh syndrome: From yeast to organoids.Journal of inherited metabolic disease · 2024Review
- SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy.Circulation · 2024Article
- A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy.EMBO molecular medicine · 2023Article
- Article
- Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation.Nature communications · 2023Article
- Male guanine-rich RNA sequence binding factor 1 knockout mice (Grsf1Cell & bioscience · 2022Article
- Article
- Noninvasive Ophthalmic Imaging Measures Retinal Degeneration and Vision Deficits in Ndufs4-/- Mouse Model of Mitochondrial Complex I Deficiency.Translational vision science & technology · 2022Article
- Bezafibrate Rescues Mitochondrial Encephalopathy in Mice via Induction of Daily Torpor and Hypometabolic State.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Article
- Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention.Brain : a journal of neurology · 2022Review
- Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice.Scientific reports · 2022Article
- Sub-Cellular Metabolomics Contributes Mitochondria-Specific Metabolic Insights to a Mouse Model of Leigh Syndrome.Metabolites · 2021Article
- Analysis of SINE Families B2, Dip, and Ves with Special Reference to Polyadenylation Signals and Transcription Terminators.International journal of molecular sciences · 2021Article
- The Ubiquitin-Specific Protease Usp7, a Novel Merkel Cell Polyomavirus Large T-Antigen Interaction Partner, Modulates Viral DNA Replication.Journal of virology · 2020Article
- Mitochondrial Proteome of Affected Glutamatergic Neurons in a Mouse Model of Leigh Syndrome.Frontiers in cell and developmental biology · 2020Article
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Authors and funding
20 authors at 8 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Eukaryotic cells generate energy in the form of ATP, through a network of mitochondrial complexes and electron carriers known as the oxidative phosphorylation system. In mammals, mitochondrial complex I (CI) is the largest component of this system, comprising 45 different subunits encoded by mitochondrial and nuclear DNA. Humans diagnosed with mutations in the gene NDUFS4, encoding a nuclear DNA-encoded subunit of CI (NADH dehydrogenase ubiquinone Fe-S protein 4), typically suffer from Leigh syndrome, a neurodegenerative disease with onset in infancy or early childhood. Mitochondria from NDUFS4 patients usually lack detectable NDUFS4 protein and show a CI stability/assembly defect. Here, we describe a recessive mouse phenotype caused by the insertion of a transposable element into Ndufs4, identified by a novel combined linkage and expression analysis. Designated Ndufs4(fky), the mutation leads to aberrant transcript splicing and absence of NDUFS4 protein in all tissues tested of homozygous mice. Physical and behavioral symptoms displayed by Ndufs4(fky/fky) mice include temporary fur loss, growth retardation, unsteady gait, and abnormal body posture when suspended by the tail. Analysis of CI in Ndufs4(fky/fky) mice using blue native PAGE revealed the presence of a faster migrating crippled complex. This crippled CI was shown to lack subunits of the "N assembly module", which contains the NADH binding site, but contained two assembly factors not present in intact CI. Metabolomic analysis of the blood by tandem mass spectrometry showed increased hydroxyacylcarnitine species, implying that the CI defect leads to an imbalanced NADH/NAD(+) ratio that inhibits mitochondrial fatty acid β-oxidation.
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