Abstract
The xenotopic expression of the alternative oxidase AOX from the tunicate Ciona intestinalis in diverse models of human disease partially alleviates the phenotypic effects of mitochondrial respiratory chain defects. AOX is a non-proton pumping, mitochondrial inner membrane-bound, single-subunit enzyme that can bypass electron transport through the cytochrome segment, providing an additional site for ubiquinone reoxidation and oxygen reduction upon respiratory chain overload. We set out to investigate whether AOX expression in Drosophila could counteract the effects of mitochondrial DNA (mtDNA) replication defects caused by disturbances in the mtDNA helicase or DNA polymerase γ. We observed that the developmental arrest imposed by either the expression of mutant forms of these enzymes or their knockdown was not rescued by AOX. Considering also the inability of AOX to ameliorate the phenotype of tko25t, a fly mutant with mitochondrial translation deficiency, we infer that this alternative enzyme may not be applicable to cases of mitochondrial gene expression defects. Finding the limitations of AOX applicability will help establish the parameters for the future putative use of this enzyme in gene therapies for human mitochondrial diseases.
Highlights
Mutations in the human genes TWNK and POLG, respectively encoding the mitochondrial replicative DNA helicase Twinkle and the catalytic subunit of the mitochondrial replicase pol γ, are associated with diverse human diseases, as well as with aging
The fact that oxidative phosphorylation (OXPHOS) is often affected in mitochondrial diseases does provide a possible common target for therapeutic interventions: the respiratory chain (RC)
Considering the earlier finding that alternative oxidase (AOX) can ameliorate the phenotype of pol γ-depleted flies, which are defective in mitochondrial DNA (mtDNA) replication, we hypothesized that AOX could have the same effect in flies with defects in the Drosophila homologue of Twinkle
Summary
Mutations in the human genes TWNK and POLG, respectively encoding the mitochondrial replicative DNA helicase Twinkle and the catalytic subunit of the mitochondrial replicase pol γ, are associated with diverse human diseases, as well as with aging. They underlie cases of Progressive External Ophthalmoplegia (PEO) and Alper’s syndrome, for which mitochondrial DNA (mtDNA) depletion, deletions and/or point mutations are frequently observed[1,2,3,4]. Our data shows that AOX does not rescue developmental lethality, nor alter the biochemical and molecular parameters associated with Twinkle and pol γ mutations or knockdown This restricts the potential therapeutic use of AOX to specific types of mitochondrial dysfunction
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