Table 1 Relationship between NDUFA4 expression and development of some diseases
Classification | Disease | Expression of NDUFA4 | Regulation result | Conclusion | References |
|---|---|---|---|---|---|
Cancers | Colorectal cancer (CRC) | Overexpression | Promotes the in vitro growth of human CRC cancer cells with altered mitochondrial energy metabolism | NDUFA4 assumes a pivotal role in the development of human CRC by regulating the OXPHOS and glycolysis, as well as other molecules, indicating its complex role in human CRC | |
| Â | Â | Low expression | Inhibits the in vitro growth of human CRC cancer cells | Â | Â |
| Â | Gastric cancer (GC) | Overexpression | Promotes GC cell growth | NDUFA4 assumes a pivotal role in the development of GC and participates in the regulation of other molecules, reflecting its potential application value in the prognosis and treatment of GC | |
| Â | Â | Low expression | Inhibits cancer growth | Â | Â |
| Â | Esophageal squamous cell carcinoma (ESCC) | Overexpression | Inhibit the proliferation and invasion of ESCC and alters the cell cycle distribution | NDUFA4 is closely related to ESCC through regulation of the growth and metastasis of human ESCC cells | [37] |
|  |  | Low expression | – |  |  |
| Â | Pancreatic adenocarcinoma (PAAD) | Overexpression | Improve the proliferation of human pancreatic cancer cells and promote the growth of cancer cells in vivo | NDUFA4 is upregulated in pancreatic cancer tissues and negatively correlated with patient survival | [38] |
| Â | Â | Low expression | Induces the opposite effect | Â | Â |
| Â | Lung cancer (LCA) | Overexpression | Increases the growth and metastasis of human lung cancer cells | NDUFA4 promotes the growth and metastasis of human lung cancer cells and leads to alterations in Akt and Erk pathway signaling. The optimized TTF-1 promoter can more effectively manipulate miR-7 to affect the growths of human non-small cell lung cancer (NSCLC) cells via inhibiting NDUFA4 expression | |
| Â | Â | Low expression | Induces the reduction in human lung cancer cell growth and metastasis due to miR-7 expression | Â | Â |
| Â | Breast cancer (BC) | Overexpression | Enhances OXPHOS pathway and increases ATP consumption | Metabolic conversion is a key alteration in the ecological niche of breast cancer cells prior to preparation for metastasis | [40] |
| Â | Renal cell carcinoma (RCC) | Overexpression | Higher expression in distal tubules | NDUFA4 is differentially expressed in renal cell carcinoma and is associated with cancer-specific survival | [41] |
| Â | Â | Low expression | NDUFA4 mRNA and protein downregulation | Â | Â |
| Â | Head and neck paraganglioma (HNPGL) | Overexpression | Promotes the assembly of mitochondrial respiratory chain complexes, increases ATP production, and elevates cancer cell viability | NDUFA4 promotes the progression of HNPGL | [42] |
| Â | Â | Low expression | Impairs the assembly of mitochondrial respiratory chain complexes and decreases the production of ATP and reduced cancer cell viability | Â | Â |
Genetic diseases | Diabetic obesity | Low expression | Impairs glucose uptake and mitochondrial complex IV activity | Adipose tissue macrophage-derived miR-210 regulates glucose uptake and mitochondrial complex IV activity by targeting NDUFA4 expression to promote the development of obesity in diabetic mice | [43] |
| Â | Â | Overexpression | Opposite of above | Â | Â |
| Â | Diet-induced diabetes | Low expression | Enhances oxidative stress | NDUFA4 mutation is directly associated with mitochondrial dysfunction, which, together with SDF2L1 deletion expression and diabetic diet, leads to enhanced oxidative stress, preventing mitochondrial ATP production and thereby impairing the ability of the pancreas to secrete insulin and leading to the development of diabetes | |
Heterogeneous diseases | Alzheimer's disease (AD) | Expression | NDUFA4 is associated with mitochondrial dysfunction in the pathogenesis of AD | Complex IV of the mitochondrial electron transport chain (cytochrome c oxidase, COX) is particularly vulnerable in AD. mRNA levels of NDUFA4 correlate significantly with Aβ plaque load in the hippocampus of AD mice | |
| Â | Azoospermia (AS) | Overexpression | Reduces the level of DJ-1 (a protein highly associated with male sterility) | DJ-1 deficiency in testicular tissue may be closely related to the localization of NDUFS3 and the level of NDUFA4, leading to abnormalities in mitochondrial energy metabolism and multiple other metabolic pathways | [51] |
| Â | Amyotrophic lateral sclerosis (ALS) | NDUFA4 binds to receptor expression enhancing protein (REEP1) | Maintains mitochondrial complex IV function | Motor function is preserved in SOD1 G93A mice | [52] |
Infectious diseases | Viral infections (Zika virus ZIKV, dengue virus, SARS-CoV-2) | Low expression | Leads mitochondrial stress, which leads to mtDNA leakage and the upregulation of type I interferon signaling. Isogenic human induced pluripotent stem cell (hiPSC) lines carrying nonrisk alleles of single nucleotide polymorphisms (SNPs) or cis-regulatory region deletions are less sensitive to viral infection | NDUFA4 is identified as a previously unknown susceptibility locus for viral infection | [53] |
Body functions | Neurons | Overexpression | Inhibits miR-145a-5p expression can promote neuronal proliferation and inhibit neuronal apoptosis in vitro | NDUFA4 promotes the proliferation and inhibits the apoptosis of neurons by inhibiting miR-145a-5p | [28] |
| Â | Â | Low expression | Enhances Mir-145a-5p expression, thereby inhibiting the proliferation of neurons and promoting their apoptosis | Â | Â |
| Â | Heart function | Expression | Sustains mitochondrial function | CLOCK regulates adaptive stress responses critical for cell survival by transcriptionally orchestrating mitochondrial quality control mechanisms in cardiomyocytes | [54] |