| Full Name | NADH:Ubiquinone Oxidoreductase Core Subunit S3 |
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| Chromosomal Location | 19p13.3 |
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| NCBI Gene ID | 4714 |
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| OMIM | 601446 |
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| Ensembl ID | ENSG00000103245 |
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| UniProt | O75489 |
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| Associated Diseases | Parkinson's Disease, Leigh Syndrome, Mitochondrial Complex I Deficiency |
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NDUFS3 (NADH:Ubiquinone Oxidoreductase Core Subunit S3) encodes a core component of mitochondrial complex I (NADH:ubiquinone oxidoreductase), the largest enzyme complex of the electron transport chain. Located on chromosome 19p13.3, NDUFS3 is essential for complex I assembly and function, and its dysfunction is linked to neurodegenerative diseases including Parkinson's disease.
The NDUFS3 gene encodes a 30 kDa iron-sulfur protein that forms part of the hydrophilic arm of mitochondrial complex I:
- Electron transfer: NDUFS3 contains [2Fe-2S] clusters that mediate electron transfer from NADH to ubiquinone.
- Complex I assembly: Essential for the assembly and stability of the entire complex I holoenzyme.
- ATP production: Critical for oxidative phosphorylation and cellular ATP generation.
- Reactive oxygen species (ROS): Dysfunction leads to increased ROS production and oxidative stress.
- Mitochondrial quality control: Regulates mitophagy and mitochondrial dynamics.
| Feature |
Details |
| Molecular weight |
~30 kDa |
| Protein class |
Iron-sulfur protein (2Fe-2S) |
| Location in Complex I |
30 kDa subunit, Q module |
| Cofactors |
1 [2Fe-2S] center |
- Evidence: NDUFS3 deficiency and complex I dysfunction are hallmark features of sporadic and genetic PD
- Mechanism:
- Impaired complex I activity leads to reduced ATP and increased ROS in dopaminergic neurons
- PINK1/Parkin mitophagy pathway is affected by complex I dysfunction
- Mitochondrial dysfunction precedes clinical symptoms in PD models
- Therapeutic targeting: CoQ10 and complex I-targeted therapies are in development
- Inheritance: Autosomal recessive
- Clinical features: Subacute necrotizing encephalomyelopathy, developmental regression, movement disorders
- Mechanism: Severe complex I deficiency impairs energy metabolism in the brain
- Phenotype: Variable multisystem disease with encephalomyopathy, cardiomyopathy
- NDUFS3 mutations: Cause isolated complex I deficiency
NDUFS3 is expressed in all tissues with high energy demands:
- Brain: High expression in substantia nigra (dopaminergic neurons), cerebellum, hippocampus
- Heart: High expression in cardiac muscle
- Skeletal muscle: High expression
Expression is regulated by mitochondrial biogenesis factors including PGC-1α.
- Kirby et al., NDUFS3 mutations cause complex I deficiency (2004)
- Schapira, Mitochondrial dysfunction in Parkinson's disease (2012)
- Gandhi et al., NDUFS3 and early-onset Parkinson's disease (2009)