Unknown,Transcriptomics,Genomics,Proteomics

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Partial phenotypic rescue of the Sesb1 mitochondrial ANT1 disease model in Drosophila

ABSTRACT: Study of gene expression patterns of Drosophila melanogaster Sesb1 mutants compared to wild type Inbreeding under stressful conditions inevitably results in the selection of compensatory alleles of many genes. In order to avoid such issues, and thus determine the global effects on gene expression of the Sesb1 mutation in a truly unselected and 'wild-type' background, we outbred Sesb1 over more than 10 generations by back-crossing to each of two commonly used wild-type strains, Canton S and Oregon R. Subsequent to this backcrossing, Sesb1 was maintained in each background using a balancer chromosome. These stocks were then used to generate a Sesb1 mutant F1 generation, by crossing virgin Canton S Sesb1. homozygous mutant females with Oregon R Sesb1 males. For comparison, we generated otherwise isogenic wild-type F1 progeny by crossing virgin Canton S wild-type females with Oregon R wild-type males. Progeny was collected on the day of eclosion and aged for one day after which the RNA was isolated with Trizol. The quality of the RNA was analyzed with a spectrophotometer.

ORGANISM(S): Drosophila melanogaster

SUBMITTER: Suvi Vartiainen

PROVIDER: E-GEOD-55187 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Phenotypic rescue of a Drosophila model of mitochondrial ANT1 disease.

Vartiainen Suvi S Chen Shanjun S George Jack J Tuomela Tea T Luoto Kaisa R KR O'Dell Kevin M C KM Jacobs Howard T HT

Disease models & mechanisms 20140508 6

A point mutation in the Drosophila gene that codes for the major adult isoform of adenine nuclear translocase (ANT) represents a model for human diseases that are associated with ANT insufficiency [stress-sensitive B(1) (sesB(1))]. We characterized the organismal, bioenergetic and molecular phenotype of sesB(1) flies then tested strategies to compensate the mutant phenotype. In addition to developmental delay and mechanical-stress-induced seizures, sesB(1) flies have an impaired response to soun ...[more]

PMID: 24812436

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Project description:Background: A point mutation in the Drosophila gene technical knockout (tko), encoding mitoribosomal protein S12, provokes a phenotype of respiratory chain deficiency, developmental delay and neurological abnormalities similar to those presented in many human mitochondrial disorders, as well as defective courtship behaviour. Results: Transcriptome-wide analysis of gene expression in tko25t mutant flies revealed systematic, compensatory changes in expression of genes connected with metabolism, including upregulation of lactate dehydrogenase and of many genes involved in the catabolism of fats and proteins, the TCA cycle and anaplerotic pathways feeding into it. Gut-specific enzymes involved in the primary mobilization of dietary fat and protein, as well as a number of transport functions, were strongly upregulated, consistent with the idea that OXPHOS dysfunction is perceived physiologically as a starvation for particular biomolecules. Many stress-response genes were also induced. Other changes may reflect a signature of developmental delay. There was also down-regulation of genes connected with reproduction, including gametogenesis, especially in females, and courtship behaviour in males. This might represent a programmed response to a mitochondrially generated starvation signal. Although human sexual behaviour is not known to respond to mitochondrial dysfunction, the underlying signaling pathway, if conserved, could influence many physiological processes in response to nutritional stress. Transcriptomic analysis suggested the possible involvement of the Akt1/sgg signaling pathway(s). Conclusions: The transformation of metabolism in response to mitochondrial dysfunction, including digestive and absorptive functions, gives important clues as to how novel therapeutic strategies for mitochondrial disorders might be developed. Experiment Overall Design: Crosses and maintenance: Inbreeding under stressful conditions inevitably results in the selection of compensatory alleles of many genes. In order to avoid such issues, and thus determine the global effects on gene expression of the tko25t mutation in a truly unselected and 'wild-type' background, we outbred tko25t over more than 10 generations by back-crossing to each of two commonly used wild-type strains, Canton S and Oregon R. Subsequent to this backcrossing, tko25t was maintained in each background using a balancer chromosome. These stocks were then used to generate a tko25t mutant F1 generation, by crossing virgin Canton S tko25t homozygous mutant females with Oregon R tko25t males. For comparison, we generated otherwise isogenic wild-type F1 progeny by crossing virgin Canton S wild-type females with Oregon R wild-type males. Experiment Overall Design: Samples: Both tko25t and wild-type Drosophila adult flies of both sexes were collected and aged to 1 day old prior to RNA extraction and hybridization on Affymetrix microarrays. We extracted RNA from 3 independent such crosses. Experiment Overall Design: Comparative analysis: Data analysis for each gene in the array compared each tko25t mutant RNA isolate with each wild-type RNA isolate from flies of the given sex, generating 9 comparative measurements, over which the statistical analysis was performed.

Dataset Information

Partial phenotypic rescue of the Sesb1 mitochondrial ANT1 disease model in Drosophila

Publications

Phenotypic rescue of a Drosophila model of mitochondrial ANT1 disease.

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