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A Deep-sequencing-assisted, Spontaneous Suppressor Screen in the Fission Yeast Schizosaccharomyces pombe
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A cytoplasmic suppressor of a nuclear mutation affecting mitochondrial functions in Drosophila

Shanjun Chen1, Marcos T Oliveira, Alberto Sanz

  • 1Institute of Biomedical Technology and Tampere University Hospital, FI-33014 University of Tampere, Finland.

Genetics
|August 2, 2012
PubMed

Insights

Mitochondrial disease phenotypes can be suppressed by genetic factors in the nuclear or mitochondrial DNA. This study identified mitochondrial DNA variations and Spargel (PGC1α) as key suppressors of mitochondrial dysfunction in Drosophila.

Area of Science:

  • Genetics
  • Mitochondrial Biology
  • Developmental Biology

Background:

  • Oxidative phosphorylation (OXPHOS) phenotypes are influenced by both nuclear and mitochondrial DNA (mtDNA).
  • Variable clinical presentations in mitochondrial disease patients suggest genetic modifiers in the 'other' genome, but their identity and mechanisms remain unclear.
  • The Drosophila melanogaster nuclear mutant tko(25t) exhibits mitochondrial disease-like phenotypes, including developmental delay and seizures, due to impaired mitochondrial protein synthesis.

Purpose of the Study:

  • To investigate cytoplasmic suppression of the mitochondrial disease-like phenotype in the tko(25t) Drosophila mutant.
  • To identify the genetic determinants and molecular mechanisms underlying this suppression.
  • To explore the role of mitochondrial DNA (mtDNA) variations and mitochondrial biogenesis in modulating disease phenotypes.

Main Methods:

  • Phenotypic analysis of the tko(25t) nuclear mutant and suppressor strains.
  • Measurement of mtDNA copy number and expression of mitochondrial biogenesis factors (porin, Spargel/PGC1α).
  • Genetic analysis of mtDNA coding and noncoding regions, including the origin of replication.
  • Investigation of the effect of Wolbachia infection on suppression.

Main Results:

  • Cytoplasmic factors suppressed the tko(25t) mitochondrial disease-like phenotype.
  • Suppression correlated with increased mtDNA copy number and enhanced mitochondrial biogenesis, evidenced by elevated porin and Spargel (PGC1α) levels.
  • Overexpression of Spargel phenocopied the suppressor effect, identifying it as a key target.
  • Suppressor strain mtDNAs exhibited distinct coding-region polymorphisms and variations in the noncoding region.
  • Cytoplasm from Wolbachia-infected strains showed a suppressor effect, unlike uninfected strains.

Conclusions:

  • Mitochondrial DNA genotype plays a critical role in modulating mitochondrial disease phenotypes.
  • Spargel (PGC1α) is a key mediator of mitochondrial biogenesis and phenotypic suppression.
  • Chronic Wolbachia infection may have selected for enhanced mitochondrial fitness under metabolic stress, providing a model for nuclear-mitochondrial interactions in disease.

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