ND1 (MT-ND1): Mitochondrial NADH Dehydrogenase Subunit 1
A core subunit of mitochondrial complex I, implicated in mitochondrial diseases and cancer metabolism.
Gene Information Card
| Symbol | MT-ND1 |
|---|---|
| Full Name | Mitochondrially Encoded NADH:Ubiquinone Oxidoreductase Core Subunit 1 |
| Gene Type | Protein coding (mitochondrial DNA) |
| Chromosomal Location | Mitochondrial DNA (MT), position 3307–4262 (NC_012920.1) |
| NCBI Gene ID | 4535 ncbi.nlm.nih.gov/gene/4535 |
| Ensembl ID | ENSG00000198888 |
| UniProt ID | P03886 |
| OMIM ID | 516000 |
| HGNC ID | 7455 |
| Aliases | ND1, MTND1, NADH dehydrogenase subunit 1, Complex I subunit 1 |
Description
MT-ND1 encodes a 318-amino-acid protein that is a core subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase), the first enzyme of the oxidative phosphorylation (OXPHOS) electron transport chain. The protein is embedded in the inner mitochondrial membrane and participates in electron transfer from NADH to ubiquinone, contributing to proton pumping and ATP synthesis. Mutations in MT-ND1 are associated with a spectrum of mitochondrial disorders, including Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), and Leigh syndrome. Additionally, somatic mutations in MT-ND1 have been identified in various cancers, suggesting a role in tumor metabolism and progression.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Leber hereditary optic neuropathy (LHON) | Pathogenic variants (e.g., m.3460G>A) impair complex I activity, leading to reactive oxygen species (ROS) overproduction and retinal ganglion cell degeneration. | ClinVar, OMIM |
| Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) | Mutations such as m.3376G>A and m.3697G>A disrupt complex I assembly or function, causing energy deficiency and lactic acidosis. | ClinVar, OMIM |
| Leigh syndrome | Biallelic or heteroplasmic mutations (e.g., m.3481G>A) reduce complex I activity, leading to progressive neurodegeneration. | ClinVar, OMIM |
| Cancer (e.g., renal cell carcinoma, thyroid cancer) | Somatic mutations in MT-ND1 alter mitochondrial metabolism, promoting aerobic glycolysis (Warburg effect) and tumor growth. | COSMIC, literature evidence |
| Exercise intolerance and myopathy | Mutations such as m.3308T>C cause complex I deficiency, resulting in muscle weakness and exercise-induced fatigue. | ClinVar, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Heart | High (nTPM ~ 2000) | High mitochondrial density due to high energy demand |
| Skeletal Muscle | High (nTPM ~ 1800) | High mitochondrial content for oxidative metabolism |
| Liver | Moderate (nTPM ~ 800) | Moderate mitochondrial activity |
| Brain | Moderate (nTPM ~ 700) | Neurons rely on OXPHOS; expression varies by region |
| Kidney | Moderate (nTPM ~ 600) | Active transport requires ATP |
| Lung | Low (nTPM ~ 200) | Lower mitochondrial density |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | High | Cancer cells often upregulate mitochondrial biogenesis |
| HepG2 (liver cancer) | High | Hepatocytes have high mitochondrial content |
| SH-SY5Y (neuroblastoma) | Moderate | Neuronal-like cells with active OXPHOS |
| MCF7 (breast cancer) | Moderate | Hormone-responsive cells with moderate mitochondrial activity |
| A549 (lung cancer) | Low | Glycolytic phenotype with reduced OXPHOS |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| m.3460G>A (p.A52T) | Missense | ~15% of LHON cases | Impairs complex I activity and increases ROS production |
| m.3376G>A (p.E24K) | Missense | Rare (MELAS) | Disrupts complex I assembly, leading to energy deficiency |
| m.3697G>A (p.G131S) | Missense | Rare (MELAS/Leigh) | Reduces complex I activity and ATP synthesis |
| m.3308T>C (p.M1T) | Missense | Rare (myopathy) | Affects translation initiation, reducing ND1 protein levels |
| m.3481G>A (p.E59K) | Missense | Rare (Leigh syndrome) | Impairs proton pumping and complex I function |
Mutation functional classification
Loss of Function (LOF)
Most pathogenic mutations cause partial or complete loss of complex I activity, leading to reduced ATP production and increased oxidative stress.
Gain of Function (GOF)
Some mutations may enhance ROS production, acting as a gain-of-function in terms of oxidative damage, though this is not a classic gain-of-function.
Dominant Negative (DN)
Heteroplasmic mutations can exert a dominant-negative effect by incorporating mutant ND1 into complex I, disrupting the entire holoenzyme assembly.
View complete mutation data：
Gene Ontology (GO)
| • NADH dehydrogenase (ubiquinone) activity (GO:0008137) | • NADH to ubiquinone (GO:0006120) |
| • Mitochondrial inner membrane (GO:0005743) | • Oxidation-reduction process (GO:0055114) |
| • Proton transmembrane transport (GO:1902600) |
Pathways
• Oxidative phosphorylation (KEGG: hsa00190)
• Metabolic pathways (KEGG: hsa01100)
• Thermogenesis (KEGG: hsa04714)
• Parkinson disease (KEGG: hsa05012)
• Alzheimer disease (KEGG: hsa05010)
Protein Summary
The ND1 protein is a 35.6 kDa hydrophobic subunit of mitochondrial complex I, composed of 318 amino acids. It contains 8 transmembrane helices and is essential for the structural integrity of the complex. ND1 participates in the ubiquinone binding site and is involved in electron transfer. The protein is synthesized within mitochondria and requires the mitochondrial translation machinery. Defects in ND1 lead to complex I deficiency, which is a common cause of mitochondrial disorders. In cancer, ND1 mutations can alter metabolic reprogramming, contributing to tumor progression.
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