The mutations in the NFU1 gene result in the autosomal recessive hereditary disorder known as Multiple Mitochondrial Dysfunction Syndrome 1 (MMDS1). Pathogenic mutations cause the intra-mitochondrial target proteins of NFU1 (known as Nfu1 in yeast) to become dysfunctional. There have been reports of 20 NFU1 mutations to date, however the precise pathogenic mechanism of MMDS1 is yet unknown. In this study, we simulated the missense mutations identified in patients and constructed four yeast models to confirm the pathogenic relevance of these mutations in humans. We analyzed the mitochondrial phenotype of yeast cells, including their respiration and oxidative stress. Mutated yeast strains exhibited a higher frequency of small colony formation, suggesting enhanced mutability of mtDNA. There are differences in the effects of mutations at different sites on cells, and their severity may be related to the CxxC motif. Finally, we established an efficient, yeast-based method to select drugs capable of alleviating oxidative stress caused by NFU1 mutations. These yeast models are useful for studying the pathogenic association of novel mutations or rare polymorphisms in NFU1, which will provide theoretical guidance for treating MMDS1 disease or other mitochondrial diseases.

• PMID: 40233434
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Journal Article

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Liu S, Liu Y, Fan W, Zhou H, Cai H

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