Mutations in the human gene C10orf2, which encodes for the mitochondrial DNA (mtDNA) helicase, are associated with several cases of mitochondrial and neurodegenerative diseases, such as Progressive External Ophthalmoplegia (PEO), Perrault Syndrome, Infantile-Onset Spinocerebellar Ataxia (IOSCA), among others. The mtDNA helicase, also known as Twinkle, is an enzyme capable of utilizing ATP to translocate along single-stranded DNA and promote unwinding of the double-stranded DNA template during the replication process of this genome. Three mutations analogues to the ones found in the human gene (K388A, W441C e A442P) were modeled in Drosophila melanogaster, causing mtDNA replication problems, reduced respiratory chain activity, and developmental disturbances. The transgenic expression of the mitochondrial alternative oxidase (AOX) from Ciona intestinalis in D. melanogaster has proven to be effective against genetic defects caused by mitochondrial dysfunctions, which in turn can be caused by mtDNA replication problems. The goal of this project is to investigate if the expression of AOX could also alleviate or neutralize the negative effects on fly development caused by mutations in the mtDNA helicase. The appointed Master student will analyze phenotypic data such as larval/pupal viability, biochemical data such as the activity of the respiratory chain complexes, and molecular data such as mtDNA copy number. The results may help understanding the roles of AOX in buffering mitochondrial functions, in addition to help promoting treatment strategies for diseases whose molecular basis are involved with mtDNA replication.
News published in Agência FAPESP Newsletter about the scholarship: