NDUFA4, also proposed to be renamed COXFA4, is a subunit of mitochondrial respiratory chain complex IV. It is integral to mitochondrial energy metabolism via the respiratory chain-oxidative phosphorylation pathway, playing a crucial role in cellular energy production and various biological processes [3]. Genetic models, such as gene knockout mouse models, can be valuable in studying its functions.

In Ndufa4-knockout (KO) mice, abnormal histological alterations were observed in brain tissue, along with impaired spatial learning capacity and exploratory activity. Ndufa4 depletion also altered the microRNA expressional profiles of the cerebellum. Specifically, Ndufa4 promoted neuron proliferation and inhibited apoptosis by inhibiting miR-145a-5p, which directly targets and inhibits the untranslated regions of Homer1 and Ccnd2 expression [1]. In addition, NDUFA4 knockdown in PGL-626 cells (a head and neck paraganglioma cell line) impaired the assembly of mitochondrial respiratory chain complexes, decreased ATP production and cell viability, and increased cell ferroptosis. This also enhanced Metformin-mediated inhibition of head and neck paraganglioma progression in mice [2].

In conclusion, NDUFA4 is essential for mitochondrial function and energy metabolism. Model-based research, especially Ndufa4 KO mouse models, has revealed its role in neuronal regulation and cancer-related processes. Understanding NDUFA4's functions provides insights into the pathogenesis of neurological disorders and cancers, potentially offering new therapeutic targets for these diseases.

References:

1. Fu, Fang, Chen, Chen, Du, Kun, Li, Dong-Zhi, Liao, Can. 2023. Ndufa4 Regulates the Proliferation and Apoptosis of Neurons via miR-145a-5p/Homer1/Ccnd2. In Molecular neurobiology, 60, 2986-3003. doi:10.1007/s12035-023-03239-5. https://pubmed.ncbi.nlm.nih.gov/36763283/

2. Wang, Zhigang, Tao, Erxing, Chen, Yiming, Chen, Wei, Zhong, Chunlong. 2023. NDUFA4 promotes the progression of head and neck paraganglioma by inhibiting ferroptosis. In Biochemistry and cell biology = Biochimie et biologie cellulaire, 101, 523-530. doi:10.1139/bcb-2023-0018. https://pubmed.ncbi.nlm.nih.gov/37602474/

3. Pitceathly, Robert D S, Taanman, Jan-Willem. 2018. NDUFA4 (Renamed COXFA4) Is a Cytochrome-c Oxidase Subunit. In Trends in endocrinology and metabolism: TEM, 29, 452-454. doi:10.1016/j.tem.2018.03.009. https://pubmed.ncbi.nlm.nih.gov/29636225/