Biophysical and genetic analysis of iron partitioning and ferritin function in Drosophila melanogaster

Gutiérrez, Lucía; Zubow, Kristina; Nield, Jon; Gambis, Alexis; Mollereau, Bertrand; Lázaro, Francisco J.; Missirlis, Fanis

doi:10.1039/c3mt00118k

Cited by 39 publications

(45 citation statements)

References 64 publications

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“…1A). The classic mutations Po lpo (Collins and Glassman, 1969) and Aldox-1 n1 (Dickinson, 1970) (Sadraie and Missirlis, 2011) and white (Gutiérrez et al, 2013) were used as controls.…”

Section: Drosophila Culturesmentioning

confidence: 99%

The four aldehyde oxidases of Drosophila melanogaster have different gene expression patterns and enzyme substrate specificities

Marelja

Dambowsky

Bolis

et al. 2014

Journal of Experimental Biology

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In the genome of Drosophila melanogaster, four genes coding for aldehyde oxidases (AOX1-4) were identified on chromosome 3. Phylogenetic analysis showed that the AOX gene cluster evolved via independent duplication events in the vertebrate and invertebrate lineages. The functional role and the substrate specificity of the distinct Drosophila AOX enzymes is unknown. Two loss-of-function mutant alleles in this gene region, low pyridoxal oxidase (Po lpo ) and aldehyde oxidase-1 (Aldox-1 n1 ) are associated with a phenotype characterized by undetectable AOX enzymatic activity. However, the genes involved and the corresponding mutations have not yet been identified. In this study we characterized the activities, substrate specificities and expression profiles of the four AOX enzymes in D. melanogaster. We show that the Po lpo -associated phenotype is the consequence of a structural alteration of the AOX1 gene. We identified an 11-bp deletion in the Po lpo allele, resulting in a frameshift event, which removes the molybdenum cofactor domain of the encoded enzyme. Furthermore, we show that AOX2 activity is detectable only during metamorphosis and characterize a Minos-AOX2 insertion in this developmental gene that disrupts its activity. We demonstrate that the Aldox-1 n1 phenotype maps to the AOX3 gene and AOX4 activity is not detectable in our assays.

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“…1A). The classic mutations Po lpo (Collins and Glassman, 1969) and Aldox-1 n1 (Dickinson, 1970) (Sadraie and Missirlis, 2011) and white (Gutiérrez et al, 2013) were used as controls.…”

Section: Drosophila Culturesmentioning

confidence: 99%

The four aldehyde oxidases of Drosophila melanogaster have different gene expression patterns and enzyme substrate specificities

Marelja

Dambowsky

Bolis

et al. 2014

Journal of Experimental Biology

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“…When iron availability is manipulated in the diet, there is a corresponding change in the iron storage protein ferritin (Georgieva et al 1999; Jiang et al 2014; Missirlis et al 2006, 2007; Tang and Zhou 2013), which would be the second—and more flexible—way to change insect metal accumulation without affecting its physiology. However, apart from insect ferritins (Pham and Winzerling 2010), we know very little about metal storage in the case of the other metals (Gutierrez et al 2013). Excess copper, for example, frequently used as an insecticide, directly affects insect immunity (Polkki et al 2012) and readily accumulates in flies (Bettedi et al 2011), possibly bound to metallothioneins (McNulty et al 2001; Egli et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the X-chromosome of D. melanogaster can cause dramatic changes in total body zinc accumulation (Afshar et al 2013) and mutations in an iron transporter (Bettedi et al 2011), or flies heterozygous for mutations in the iron storage protein ferritin (Gutierrez et al 2013), accumulate less iron in their bodies. Similarly, flies heterozygous for mutations in Syntaxin 5 accumulate less copper (Norgate et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Conserved metallomics in two insect families evolving separately for a hundred million years

et al. 2014

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Μetal cofactors are required for enzymatic catalysis and structural stability of many proteins. Physiological metal requirements underpin the evolution of cellular and systemic regulatory mechanisms for metal uptake, storage and excretion. Considering the role of metal biology in animal evolution, this paper asks whether metal content is conserved between different fruit flies. A similar metal homeostasis was previously observed in Drosophilidae flies cultivated on the same larval medium. Each species accumulated in the order of 200 µg iron and zinc and approximately ten-fold less manganese and copper per gram dry weight of the adult insect. In this paper, data on the metal content in fourteen species of Tephritidae, which are major agricultural pests worldwide, are presented. These fruit flies can be polyphagous (e.g., Ceratitis capitata) or strictly monophagous (e.g., Bactrocera oleae) or oligophagous (e.g., Anastrepha grandis) and were maintained in the laboratory on five distinct diets based on olive oil, carrot, wheat bran, zucchini and molasses, respectively. The data indicate that overall metal content and distribution between the Tephritidae and Drosophilidae species was similar. Reduced metal concentration was observed in B. oleae. Feeding the polyphagous C. capitata with the diet of B. oleae resulted in a significant quantitative reduction of all metals. Thus, dietary components affect metal content in some Tephritidae. Nevertheless, although the evidence suggests some fruit fly species evolved preferences in the use or storage of particular metals, no metal concentration varied in order of magnitude between these two families of Diptera that evolved independently for over 100 million years.

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“…Ferritin overexpression, which likely results in depletion of readily bioavailable iron (Gutierrez et al, 2013), conferred no apparent protection to infected flies, but instead further decreased their shortened lifespan due to Wolbachia infection ( Figure 3B ). Our experiments did not discriminate between the possibility that ferritin overexpression benefited the pathogen, encouraging its propagation, or, alternatively, that ferritin overexpression on top of pathogen infection further deprived bioavailable brain iron.…”

Section: Discussionmentioning

confidence: 99%

“…Disrupted ferritin function by mutation or RNA interference (RNAi) results in embryonic or first instar larval lethality (Missirlis et al, 2007; Li, 2010; Tang and Zhou, 2013a). Overexpression of ferritin also leads to excess iron sequestration and functional iron deficiency, which does not impede development to adulthood (Missirlis et al, 2007; Gutierrez et al, 2013; Tang and Zhou, 2013a). Neuronal ferritin overexpression was found to be beneficial when flies were fed with aluminum (Wu et al, 2012), whereas glial ferritin overexpression resulted in ferritin-iron inclusions in a subset of glia of the optic lobes and mild behavioral defects with a late-onset of appearance (Kosmidis et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Behavioral decline and premature lethality upon pan-neuronal ferritin overexpression in Drosophila infected with a virulent form of Wolbachia

et al. 2014

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Iron is required for organismal growth. Therefore, limiting iron availability may be a key part of the host’s innate immune response to various pathogens, for example, in Drosophila infected with Zygomycetes. One way the host can transiently reduce iron bioavailability is by ferritin overexpression. To study the effects of neuronal-specific ferritin overexpression on survival and neurodegeneration we generated flies simultaneously over-expressing transgenes for both ferritin subunits in all neurons. We used two independent recombinant chromosomes bearing UAS-Fer1HCH, UAS-Fer2LCH transgenes and obtained qualitatively different levels of late-onset behavioral and lifespan declines. We subsequently discovered that one parental strain had been infected with a virulent form of the bacterial endosymbiont Wolbachia, causing widespread neuronal apoptosis and premature death. This phenotype was exacerbated by ferritin overexpression and was curable by antibiotic treatment. Neuronal ferritin overexpression in uninfected flies did not cause evident neurodegeneration but resulted in a late-onset behavioral decline, as previously reported for ferritin overexpression in glia. The results suggest that ferritin overexpression in the central nervous system of flies is tolerated well in young individuals with adverse manifestations appearing only late in life or under unrelated pathophysiological conditions.

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Biophysical and genetic analysis of iron partitioning and ferritin function in Drosophila melanogaster

Cited by 39 publications

References 64 publications

The four aldehyde oxidases of Drosophila melanogaster have different gene expression patterns and enzyme substrate specificities

The four aldehyde oxidases of Drosophila melanogaster have different gene expression patterns and enzyme substrate specificities

Conserved metallomics in two insect families evolving separately for a hundred million years

Behavioral decline and premature lethality upon pan-neuronal ferritin overexpression in Drosophila infected with a virulent form of Wolbachia

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