RGD Reference Report - 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.

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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.
Authors:	Leong, DW Komen, JC Hewitt, CA Arnaud, E McKenzie, M Phipson, B Bahlo, M Laskowski, A Kinkel, SA Davey, GM Heath, WR Voss, AK Zahedi, RP Pitt, JJ Chrast, R Sickmann, A Ryan, MT Smyth, GK Thorburn, DR Scott, HS
Citation:	Leong DW, etal., J Biol Chem. 2012 Jun 8;287(24):20652-63. Epub 2012 Apr 25.
RGD ID:	6484662
Pubmed:	PMID:22535952 (View Abstract at PubMed)
PMCID:	PMC3370248 (View Article at PubMed Central)
DOI:	DOI:10.1074/jbc.M111.327601 (Journal Full-text)
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 beta-oxidation.

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RGD Manual Disease Annotations Click to see Annotation Detail View

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
NDUFS4	Human	Leigh disease		NAS			RGD
Ndufs4	Mouse	Leigh disease		ISO	NDUFS4 (Homo sapiens)		RGD
Ndufs4	Rat	Leigh disease		ISO	NDUFS4 (Homo sapiens)		RGD

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Cellular Component

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Ndufs7	Rat	neuronal cell body		IDA			RGD
Ndufs7	Rat	synaptic membrane		IDA			RGD

Molecular Function

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Ndufs7	Rat	protease binding		IPI	Psen1 (Rattus norvegicus)		RGD
Ndufs7	Rat	protease binding		IPI	Ncstn (Rattus norvegicus)		RGD
Ncstn	Rat	protein binding		IPI	Ndufs7 (Rattus norvegicus)		RGD
Psen1	Rat	protein binding		IPI	Ndufs7 (Rattus norvegicus)		RGD

Objects Annotated

Genes (Rattus norvegicus)

Ncstn (nicastrin)

Ndufs4 (NADH:ubiquinone oxidoreductase subunit S4)

Ndufs7 (NADH:ubiquinone oxidoreductase core subunit S7)

Psen1 (presenilin 1)

Genes (Mus musculus)

Ndufs4 (NADH:ubiquinone oxidoreductase core subunit S4)

Genes (Homo sapiens)

NDUFS4 (NADH:ubiquinone oxidoreductase subunit S4)

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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.