Ndufaf6-KO Mouse

NDUFAF6, a mitochondrial complex I assembly factor, is crucial for the proper assembly of complex I (CI) in the electron transport chain. Defects in CI, which is a major cause of primary mitochondrial disease, can arise from issues with NDUFAF6 as it is not part of the CI holoenzyme [1]. It specifically facilitates the incorporation of NDUFS8 into CI, thereby playing a vital role in mitochondrial function and associated metabolic pathways [1].

Knockdown of NDUFAF6 in breast cancer cells using small interfering RNA showed that it reduces cell proliferation and migration ability. It also promotes apoptosis and mitophagy, accompanied by mitochondrial dysfunction and changes in cellular metabolism. This indicates that NDUFAF6 may be a potential molecular target for breast cancer therapy [2].

In addition, in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations, patient mutations were associated with the absence of the NDUFAF6 protein, reduced activity and assembly of mature complex I in fibroblasts. The mutant phenotype was rescued by the canonical version of the NDUFAF6, suggesting NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis [3].

In summary, NDUFAF6 is essential for complex I assembly in mitochondria. Its loss-of-function in models, such as knockdown in breast cancer cells and mutations in patients with Leigh syndrome, reveals its significant role in disease-related biological processes. These findings highlight the importance of NDUFAF6 in understanding mitochondrial-related diseases like breast cancer and Leigh syndrome, and potentially offer new therapeutic directions.

References:

1. Sung, Andrew Y, Guerra, Rachel M, Steenberge, Laura H, Keck, James L, Pagliarini, David J. 2024. Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease. In Nature metabolism, 6, 1128-1142. doi:10.1038/s42255-024-01039-2. https://pubmed.ncbi.nlm.nih.gov/38720117/

2. Wu, Shang, Ma, Xindi, Zhang, Xiangmei, Su, Suwen, Liu, Yunjiang. 2024. Knockdown of NDUFAF6 inhibits breast cancer progression via promoting mitophagy and apoptosis. In Cancer biology & therapy, 26, 2445220. doi:10.1080/15384047.2024.2445220. https://pubmed.ncbi.nlm.nih.gov/39706687/

3. Baide-Mairena, Heidy, Gaudó, Paula, Marti-Sánchez, Laura, Bayona-Bafaluy, María Pilar, Pérez-Dueñas, Belén. 2019. Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood. In Molecular genetics and metabolism, 126, 250-258. doi:10.1016/j.ymgme.2019.01.001. https://pubmed.ncbi.nlm.nih.gov/30642748/