NDUFS3

NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial is an enzyme that in humans is encoded by the NDUFS3 gene on chromosome 11.^[4][5] This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone oxidoreductase (complex I). Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.^[5]

NDUFS3
Identifiers
Aliases	NDUFS3, CI-30, NADH:ubiquinone oxidoreductase core subunit S3, MC1DN8
External IDs	OMIM: 603846; MGI: 1915599; HomoloGene: 3346; GeneCards: NDUFS3; OMA:NDUFS3 - orthologs
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11p11.2 Start 47,565,336 bp[1] End 47,584,562 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in putamen mucosa of transverse colon apex of heart muscle of thigh primary visual cortex caudate nucleus left ventricle gastrocnemius muscle prefrontal cortex Brodmann area 9 n/a More reference expression data BioGPS More reference expression data
Gene ontology Molecular function oxidoreductase activity, acting on NAD(P)H protein binding electron transfer activity oxidoreductase activity NADH dehydrogenase activity NADH dehydrogenase (ubiquinone) activity Cellular component membrane mitochondrial membranes myelin sheath mitochondrial respiratory chain complex I mitochondrial matrix mitochondrion mitochondrial inner membrane respirasome nuclear body Biological process substantia nigra development negative regulation of intrinsic apoptotic signaling pathway reactive oxygen species metabolic process mitochondrial respiratory chain complex I assembly negative regulation of cell growth mitochondrial electron transport, NADH to ubiquinone cellular respiration Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4722 68349 Ensembl ENSG00000213619 ENSG00000285387 ENSMUSG00000005510 UniProt O75489 Q9DCT2 RefSeq (mRNA) NM_004551 NM_026688 RefSeq (protein) NP_004542 NP_080964 Location (UCSC) Chr 11: 47.57 – 47.58 Mb n/a PubMed search [2] [3]
Wikidata
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Structure

The NDUFS3 gene encodes a protein subunit consisting of 263 amino acids. This protein is synthesized in the cytoplasm and then transported to the mitochondria via a signal peptide. Two mutations that occur in its highly conserved C-terminal region, T145I and R199W, are causally linked to Leigh syndrome and optic atrophy. Nonetheless, despite its crucial biological role, the human NDUFS3 remains structurally poorly understood.^[6]

Function

This gene encodes one of the iron-sulfur protein (IP) components of complex I.^[5] The 45-subunit NADH:ubiquinone oxidoreductase (complex I) is the first enzyme complex in the electron transport chain of mitochondria.^[5][7] As a catalytic subunit, NDUFS3 plays a vital role in the proper assembly of complex I and is recruited to the inner mitochondrial membrane to form an early assembly intermediate with NDUFS2.^[7][8] It initiates the assembly of complex I in the mitochondrial matrix.^[6]

Cleavage of NDUFS3 by GzmA has been observed to activate a programmed cell death pathway which results in mitochondrial dysfunction and reactive oxygen species (ROS) generation. ^[9]

Clinical significance

Mutations in the NDUFS3 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.^[10][11] Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible.^[12] However, the majority of cases are caused by mutations in nuclear-encoded genes.^[13][14] It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.^[15]

NDUFS3 has also been implicated in breast cancer and ductal carcinoma and, thus, may serve as a novel biomarker for tracking cancer progression and invasiveness.^[7]

See also

• NDUFS1