Reduction of Caenorhabditis elegans frataxin increases sensitivity to oxidative stress, reduces lifespan, and causes lethality in a mitochondrial complex II mutant.
Friedreich ataxia is an autosomal recessive neurological disorder caused by deficiency of the mitochondrial protein frataxin. Studies in patient cells, mouse knockout animals, and Saccharomyces cerevisiae models have suggested several hypotheses on the frataxin function, but the full physiology of frataxin in mitochondria has not been well established yet. We have characterized the genomic structure of frh-1, the Caenorhabditis elegans frataxin gene, and we have developed a transient knockdown model of C. elegans frataxin deficiency by RNA interference. frh-1(RNAi) worms show a consistent pleiotropic phenotype that includes slow growth, lethargic behavior, egg laying defects, reduced brood size, abnormal pharyngeal pumping, and altered defecation. Lifespan is significantly reduced, and worms have increased sensitivity to oxidative stress that, in turn, might explain the reduction of longevity of the worms. We also demonstrate synthetic genetic interaction between frh-1 and mev-1, the gene encoding the succinate dehydrogenase cytochrome b subunit of complex II in mitochondria, suggesting a possible role of the C. elegans frataxin in the electron transport chain; thus, the respiratory chain might be involved in the pathogenesis of the disease. We propose that this C. elegans model may be a useful biological tool for drug screening in Friedreich ataxia.
Vázquez-Manrique
Rafael P
RP
Laboratory of Genetics and Molecular Medicine, Department of Genomics and Proteomics, Instituto de Biomedicina, CSIC, Valencia, Spain.
González-Cabo
Pilar
P
Ros
Sheila
S
Aziz
Homera
H
Baylis
Howard A
HA
Palau
Francesc
F
D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D045303:Cytochromes b; D015971:Gene Expression Regulation, Enzymologic; D005804:Genes, Lethal / Q000235:genetics*; D005838:Genotype; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008136:Longevity; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D030781:Organisms, Genetically Modified; D018384:Oxidative Stress; D010641:Phenotype; D034622:RNA Interference; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000096923:Frataxin
D029742:Caenorhabditis elegans Proteins; D045303:Cytochromes b; D033862:Iron-Binding Proteins; D013385:Succinate Dehydrogenase; D000096923:Frataxin; C472666:MEV-1 protein, C elegans