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Resources » Paper

Kropp, Peter et al. (2021) International Worm Meeting "Allele-specific effects of mitochondrial dysfunction: A C. elegans model of Multiple Mitochondrial Dysfunctions Syndrome 1"

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  • Comments on Kropp, Peter et al. (2021) International Worm Meeting "Allele-specific effects of mitochondrial dysfunction: A C. elegans model of Multiple Mitochondrial Dysfunctions Syndrome 1" (0)

  • Overview

    Status:
    Publication type:
    Meeting_abstract
    WormBase ID:
    WBPaper00062741

    Kropp, Peter, Wu, Jing, Sack, Michael, & Golden, Andy (2021). Allele-specific effects of mitochondrial dysfunction: A C. elegans model of Multiple Mitochondrial Dysfunctions Syndrome 1 presented in International Worm Meeting. Unpublished information; cite only with author permission.

    Multiple mitochondrial dysfunctions syndrome 1 (MMDS1) is a neurodegenerative and pediatric fatal disease of the Iron-Sulphur cluster (ISC) biogenesis pathway. ISCs are essential cofactors of many proteins with a broad range of cellular functions. MMDS1 is caused by mutations the factor NFU1 that is responsible for trafficking ISCs to the appropriate mitochondrial target proteins. I hypothesized that in depth analyses of patient-specific NFU1 variations would reveal previously unappreciated roles for this factor in ISC delivery and a clearer connection between the genetics of NFU1 variants and clinical presentations of MMDS1. Using the nematode Caenorhabditis (C.) elegans, I have recreated five MMDS1 patient-specific variants of NFU1 in its ortholog nfu-1. By using C. elegans I have been able to investigate complex metabolic and multicellular phenotypes that are highly relevant to MMDS1-individuals. Analyses of these variants includes molecular, biochemical, cellular, and physiological approaches which reveal an allelic series of phenotypic severity. There are significant decreases in mitochondrial function and extensive, albeit insufficient, compensatory changes in alternative metabolic pathways. A balance between up-regulation of glycolysis and fatty acid oxidation is regulated by the transcription factors DAF-16 and its downstream effector NHR-49. Additionally, oxidative stress caused by the apparent mishandling of ISCs appears to have a significant role in the phenotypic progression. Most notably, each of the five patient-specific alleles demonstrates unique differences in the causes of metabolic and oxidative stress due to impaired ISC mishandling. Therefore, by modeling MMDS1 in C. elegans, I have been able to distinguish differences between pathogenic variants in nfu-1 which lead to complex and multicellular responses.

    Affiliations:
    - National Heart, Blood, and Lung Institute, NIH, Bethesda, MD
    - National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD


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