RRC ID 75991
Author Kropp PA, Wu J, Reidy M, Shrestha S, Rhodehouse K, Rogers P, Sack MN, Golden A.
Title Allele-specific mitochondrial stress induced by Multiple Mitochondrial Dysfunctions Syndrome 1 pathogenic mutations modeled in Caenorhabditis elegans.
Journal PLoS Genet
Abstract Multiple Mitochondrial Dysfunctions Syndrome 1 (MMDS1) is a rare, autosomal recessive disorder caused by mutations in the NFU1 gene. NFU1 is responsible for delivery of iron-sulfur clusters (ISCs) to recipient proteins which require these metallic cofactors for their function. Pathogenic variants of NFU1 lead to dysfunction of its target proteins within mitochondria. To date, 20 NFU1 variants have been reported and the unique contributions of each variant to MMDS1 pathogenesis is unknown. Given that over half of MMDS1 individuals are compound heterozygous for different NFU1 variants, it is valuable to investigate individual variants in an isogenic background. In order to understand the shared and unique phenotypes of NFU1 variants, we used CRISPR/Cas9 gene editing to recreate exact patient variants of NFU1 in the orthologous gene, nfu-1 (formerly lpd-8), in C. elegans. Five mutant C. elegans alleles focused on the presumptive iron-sulfur cluster interaction domain were generated and analyzed for mitochondrial phenotypes including respiratory dysfunction and oxidative stress. Phenotypes were variable between the mutant nfu-1 alleles and generally presented as an allelic series indicating that not all variants have lost complete function. Furthermore, reactive iron within mitochondria was evident in some, but not all, nfu-1 mutants indicating that iron dyshomeostasis may contribute to disease pathogenesis in some MMDS1 individuals.
Volume 17(8)
Pages e1009771
Published 2021-8-1
DOI 10.1371/journal.pgen.1009771
PMID 34449775
PMC PMC8428684
MeSH Alleles Animals Caenorhabditis elegans / genetics Caenorhabditis elegans Proteins / genetics Carrier Proteins / genetics Carrier Proteins / metabolism Disease Models, Animal Iron / metabolism Iron-Sulfur Proteins / genetics* Iron-Sulfur Proteins / metabolism* Mitochondria / genetics Mitochondrial Diseases / genetics* Mitochondrial Diseases / physiopathology Mitochondrial Proteins / genetics Mutation Phenotype Protein Conformation Protein Multimerization Stress, Physiological / genetics Sulfur / metabolism
C.elegans tmC5