Gene dosage and selective expression modify phenotype in a Drosophila model of human mitochondrial disease.

Human mitochondrial disease manifests with a wide range of clinical phenotypes of varying severity. To create a model for these disorders, we have manipulated the Drosophila gene technical knockout, encoding mitoribosomal protein S12. Various permutations of endogenous and transgenic alleles create a range of phenotypes, varying from larval developmental arrest through to mild neurological defects in the adult, and also mimic threshold effects associated with human mtDNA disease.

Coordinated decrease of the expression of the mitochondrial and nuclear complex I genes in a mitochondrial mutant of Drosophila.

We have studied a mutant strain of Drosophila in which 80% of the mitochondrial DNA molecules have lost over 30% of their coding region through deletion. This deletion affects genes encoding five subunits of complex I of the respiratory chain (NADH:ubiquinone oxidoreductase). The enzymatic activity of complex I in the mutant strain is half that in the wild strain, but ATP synthesis is unaffected.

The nuclear genome of a Drosophila mutant strain increases the frequency of rearranged mitochondrial DNA molecules.

We studied a mutant strain of Drosophila subobscura, in which 80% of the mitochondrial genomes (mtDNA) have lost over 30% of the coding region. The mutation is stable and is transmitted identically to offspring. The putative role of the mutant nuclear genome in the production of rearranged mtDNA was investigated using reciprocal crosses, to place the mitochondria of the wild strain in a mutant nuclear context.

The nuclear genome is involved in heteroplasmy control in a mitochondrial mutant strain of Drosophila subobscura.

Most (78%) mitochondrial genomes in the studied mutant strain of Drosophila subobscura have undergone a large-scale deletion (5 kb) in the coding region. This mutation is stable, and is transmitted intact to the offspring. This animal model of major rearrangements of mitochondrial genomes can be used to analyse the involvement of the nuclear genome in the production and maintenance of these rearrangements.