Ndufs7-KO Mouse

NDUFS7, also known as NADH dehydrogenase Fe-S protein 7, is a crucial subunit of mitochondrial respiratory chain complex I [4,5,6,7]. Complex I is involved in oxidative phosphorylation (OXPHOS), a key metabolic pathway for generating ATP in cells [2]. Thus, NDUFS7 is of great biological importance in energy production processes. Genetic models, such as Drosophila melanogaster, can be valuable for studying NDUFS7 [1].

In dogs with Leigh syndrome, a missense variant in NDUFS7 (c.535G > A or p.(Val179Met)) was identified, co-segregating with the disease phenotype in the investigated litter. In a Drosophila melanogaster model, overexpression of wild-type NDUFS7 partially rescued the lethality upon knockdown of the fly ortholog ND-20, while the mutant overexpression did not, indicating the pathogenicity of the identified variant [1]. In HEK293T cells, mutation of NDUFS7 led to reduced cell proliferation, elevated cell death, and increased oxidative stress susceptibility. Upregulation of SLC7A11 mitigated cell death from NDUFS7 deficiency by enhancing cystine import and promoting GSH biosynthesis [3]. In pancreatic cancer, a first-in-class small-molecule NDUFS7 antagonist (DX2-201) inhibited OXPHOS, and a metabolically stable analogue (DX3-213B) showed efficacy in a syngeneic model. A pV91M mutation in NDUFS7 was found in clones resistant to DX2-201, indicating its drug-binding site [2].

In conclusion, NDUFS7 is essential for the proper function of mitochondrial complex I and energy production via OXPHOS. Studies using model organisms and cell lines have revealed its role in diseases such as Leigh syndrome, pancreatic cancer, and in cell survival under oxidative stress conditions. These findings provide insights into the pathogenic mechanisms of related diseases and potential therapeutic strategies [1,2,3].

References:

1. Christen, Matthias, Gregor, Anne, Gutierrez-Quintana, Rodrigo, Zweier, Christiane, Leeb, Tosso. 2024. NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model. In Scientific reports, 14, 2975. doi:10.1038/s41598-024-53314-7. https://pubmed.ncbi.nlm.nih.gov/38316835/

2. Xu, Yibin, Xue, Ding, Kyani, Armita, Ljungman, Mats, Neamati, Nouri. 2023. First-in-Class NADH/Ubiquinone Oxidoreductase Core Subunit S7 (NDUFS7) Antagonist for the Treatment of Pancreatic Cancer. In ACS pharmacology & translational science, 6, 1164-1181. doi:10.1021/acsptsci.3c00069. https://pubmed.ncbi.nlm.nih.gov/37588763/

3. Chen, Jieli, Gao, Liuze. 2024. SLC7A11-mediated cystine import protects against NDUFS7 deficiency-induced cell death in HEK293T cells. In Biochemical and biophysical research communications, 723, 150178. doi:10.1016/j.bbrc.2024.150178. https://pubmed.ncbi.nlm.nih.gov/38823363/

4. Pronicka, Ewa, Piekutowska-Abramczuk, Dorota, Ciara, Elżbieta, Krajewska-Walasek, Małgorzata, Płoski, Rafał. 2016. New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre. In Journal of translational medicine, 14, 174. doi:10.1186/s12967-016-0930-9. https://pubmed.ncbi.nlm.nih.gov/27290639/

5. Rhein, Virginie F, Carroll, Joe, Ding, Shujing, Fearnley, Ian M, Walker, John E. 2016. NDUFAF5 Hydroxylates NDUFS7 at an Early Stage in the Assembly of Human Complex I. In The Journal of biological chemistry, 291, 14851-60. doi:10.1074/jbc.M116.734970. https://pubmed.ncbi.nlm.nih.gov/27226634/

6. Oikarainen, Jaakko, Hinttala, Reetta, Nayebzadeh, Naemeh, Suo-Palosaari, Maria, Uusimaa, Johanna. 2025. Novel intronic variant in NDUFS7 gene results in mitochondrial complex I assembly defect with early basal ganglia and midbrain involvement with progressive neuroimaging findings. In Mitochondrion, 81, 102007. doi:10.1016/j.mito.2025.102007. https://pubmed.ncbi.nlm.nih.gov/39894241/

7. Lebon, Sophie, Minai, Limor, Chretien, Dominique, Bonnefont, Jean-Paul, Rötig, Agnès. 2007. A novel mutation of the NDUFS7 gene leads to activation of a cryptic exon and impaired assembly of mitochondrial complex I in a patient with Leigh syndrome. In Molecular genetics and metabolism, 92, 104-8. doi:. https://pubmed.ncbi.nlm.nih.gov/17604671/