NDUFS2: A Core Subunit of Mitochondrial Complex I
Essential for oxidative phosphorylation and linked to mitochondrial disorders
Gene Information Card
| Symbol | NDUFS2 |
|---|---|
| Full Name | NADH:ubiquinone oxidoreductase core subunit S2 |
| Gene Type | Protein coding |
| Chromosomal Location | 1q23.3 |
| NCBI Gene ID | 4720 ncbi.nlm.nih.gov/gene/4720 |
| Ensembl ID | ENSG00000158864 |
| UniProt ID | O75306 |
| OMIM ID | 602985 |
| HGNC ID | 7708 |
| Aliases | CI-49, CI-49kD, NDUFS2, FLJ12118 |
Description
NDUFS2 encodes a 49 kDa core subunit of mitochondrial NADH:ubiquinone oxidoreductase (Complex I), the first enzyme of the electron transport chain. This subunit is essential for complex I assembly and catalytic activity, transferring electrons from NADH to ubiquinone. Mutations in NDUFS2 are associated with mitochondrial complex I deficiency, leading to Leigh syndrome, cardiomyopathy, and other early-onset neurological disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Mitochondrial complex I deficiency, nuclear type 6 (MC1DN6) | Loss-of-function mutations impair complex I assembly and activity, reducing ATP production and increasing oxidative stress. | OMIM #618232; ClinVar pathogenic variants |
| Leigh syndrome | Biallelic NDUFS2 mutations disrupt mitochondrial respiration in the brainstem and basal ganglia, causing progressive neurodegeneration. | Case reports in NCBI PubMed |
| Cardiomyopathy, hypertrophic | Complex I deficiency due to NDUFS2 mutations leads to energy depletion in cardiac muscle, resulting in hypertrophic remodeling. | ClinVar and literature review |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Heart | 28.5 | High |
| Skeletal muscle | 22.1 | High |
| Brain | 18.3 | Medium |
| Liver | 15.7 | Medium |
| Kidney | 14.2 | Medium |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 32.4 | High expression in embryonic kidney cells |
| HeLa | 25.8 | High expression in cervical cancer cells |
| SH-SY5Y | 20.1 | Moderate expression in neuroblastoma cells |
| HepG2 | 18.9 | Moderate expression in liver cancer cells |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.166G>A (p.Gly56Arg) | Missense | Rare | Impairs complex I assembly and activity; associated with Leigh syndrome |
| c.364A>G (p.Thr122Ala) | Missense | Rare | Reduces ubiquinone binding; linked to cardiomyopathy |
| c.1048C>T (p.Arg350Trp) | Missense | Rare | Disrupts electron transfer; causes mitochondrial complex I deficiency |
Mutation functional classification
Loss of Function (LOF)
Most pathogenic NDUFS2 mutations are loss-of-function, reducing complex I activity and ATP production.
Gain of Function (GOF)
No gain-of-function mutations reported.
Dominant Negative (DN)
No dominant-negative effects documented; all known pathogenic variants are recessive.
View complete mutation data：
Gene Ontology (GO)
| • NADH dehydrogenase (ubiquinone) activity | • mitochondrial respiratory chain complex I assembly |
| • electron transport chain | • mitochondrion |
| • oxidation-reduction process |
Pathways
• Oxidative phosphorylation (KEGG: hsa00190)
• Parkinson disease (KEGG: hsa05012)
• Non-alcoholic fatty liver disease (KEGG: hsa04932)
Protein Summary
NDUFS2 is a 49 kDa core subunit of mitochondrial Complex I, localized to the inner mitochondrial membrane. It contains a [4Fe-4S] cluster and is directly involved in the transfer of electrons from NADH to ubiquinone. The protein is essential for complex I stability and catalytic function. Defects in NDUFS2 lead to mitochondrial complex I deficiency, manifesting as Leigh syndrome, cardiomyopathy, and lactic acidosis.
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