Home » Key Scientific Articles » Insertion mutants in Drosophila melanogaster Hsc20 halt larval growth and lead to reduced iron-sulfur cluster enzyme activities and impaired iron homeostasis

Insertion mutants in Drosophila melanogaster Hsc20 halt larval growth and lead to reduced iron-sulfur cluster enzyme activities and impaired iron homeostasis

Significance Statement

 

This work together with the “Characterization of the human HSC20, an unusual DnaJ type III protein, involved in iron-sulfur cluster biogenesis” (Uhrigshardt H, Singh A, Kovtunovych G, Ghosh M, Rouault TA. Human Molecular Genetics 19:3816-34) establishes that reduction in cellular HSC20 activity affects key mitochondrial Fe-S cluster enzymes in humans, flies and yeast. Given the implication of other Fe-S cluster biogenesis genes (frataxin, ISCU, Grx5, Isd11) in human disease (for review see Rouault TA. Disease Models & Mechanisms 5:155-64) we propose that HSC20 may also constitute a – so far unidentified – human disease gene. A common observation when mitochondrial Fe-S clusters are affected is the accumulation of iron in mitochondria. It is worth highlighting that HSC20 from higher animals has a N-terminal domain with a couple of conserved Cysteine-X-X-Cysteine sequences that provide metal coordination sites whose specific function remains to be shown.

The photograph shows a partial rescue of the mutant flies, which would have otherwise died as larvae, as described in our paper.

Insertion mutants in Drosophila melanogaster Hsc20 halt larval growth and lead to reduced iron-sulfur cluster enzyme activities and impaired iron homeostasis- Global medical Discovery

 

 

 

 

 

 

 

 

Journal Reference

Uhrigshardt H, Rouault TA, Missirlis F.

J Biol Inorg Chem. 2013 Apr;18(4):441-9.

Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

 

Abstract

Despite the prominence of iron-sulfur cluster (ISC) proteins in bioenergetics, intermediary metabolism, and redox regulation of cellular, mitochondrial, and nuclear processes, these proteins have been given scarce attention in Drosophila. Moreover, biosynthesis and delivery of iron-sulfur cluster to target proteins requires a highly regulated molecular network that spans different cellular compartments. The only Drosophila ISC biosynthetic protein studied to date is frataxin, in attempts to model Friedreich’s ataxia, a disease arising from reduced expression of the human frataxin homologue. One of several proteins involved in iron-sulfur cluster biogenesis is heat shock protein cognate 20 (Hsc20). Here we characterize two piggyBac insertion mutants in Drosophila Hsc20 that display larval growth arrest and deficiencies in aconitase and succinate dehydrogenase activities, but not in isocitrate dehydrogenase activity; phenotypes also observed with ubiquitous frataxin RNA interference. Furthermore, a disruption of iron homeostasis in the mutant flies was evidenced by an apparent reduction in induction of intestinal ferritin with ferric iron accumulating in a subcellular pattern reminiscent of mitochondria. These phenotypes were specific to intestinal cell types that regulate ferritin expression, but were notably absent in the iron cells where ferritin is constitutively expressed and apparently translated independently of iron regulatory protein 1A. Hsc20 mutant flies represent an independent tool to disrupt iron-sulfur cluster biogenesis in vivo without using the RNA interference machinery.

 

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