Mitochondrial DNA (mtDNA) mutations are known to cause a number of encephalomyopathies and are strongly implicated in Parkinson's disease and aging. Because the mitochondrial genome is essential for proper mitochondrial function and there are numerous copies of mtDNA per cell, deleterious mtDNA mutations often co-exist in cells with WT mitochondrial DNA, a condition known as heteroplasmy. The ratio of mutated to normal mtDNA in a given cell is believed to play a crucial role in the pathogenesis of heteroplasmic disorders, but the mechanisms that influence this ratio are unknown. The proposed studies will address the hypothesis that the mitochondrial quality control system, including the Parkinson's disease genes PINK1 and Parkin, components of the mitochondrial morphogenesis machinery, and factors that promote autophagy act to reduce the frequency of deleterious mtDNA mutations by targeting mitochondria bearing these mutations for destruction.
Four aims address this hypothesis.
The first aim i nvolves the creation of three different heteroplasmic fly lines using existing deleterious mtDNA mutants and established methods. Once these heteroplasmic strains are made, they will be used in studies to explore the influence of specific components of the mitochondrial quality control system on mtDNA mutation frequencies and on the phenotypes associated with these mtDNA mutations. Specifically, the second aim will explore the influence of two genes that have recently been shown to promote turnover of damaged mitochondria via autophagy, PINK1 and Parkin.
The third aim will explore the influence of genes that promote mitochondrial fission, since this process has been shown to occur prior to mitochondrial turnover. Finally, the fourth aim will study the influence of autophagy- promoting factors. The long-term objective of the project is to identify factors that influence heteroplasmic frequencies. This study will address fundamental aspects of heteroplasmy: can components of the mitochondrial quality control system detect mitochondria bearing deleterious mtDNA mutations? If so, what sorts of mtDNA defects can the quality control system detect? My experiments should advance our understanding of the factors that remove mitochondrial DNA mutations and this insight could ultimately lead to the development of treatments for pathological conditions caused by mtDNA mutations, including mitochondrial encephaloymyopathies and Parkinson's disease.
The proposal aims to identify and explore factors that decrease mitochondrial DNA mutations of which none are currently known. These studies will potentially impact diseases caused by mitochondrial DNA mutations, including inherited mitochondrial encephalomyopathies, aging, and Parkinson's disease.
| Burman, Jonathon L; Itsara, Leslie S; Kayser, Ernst-Bernhard et al. (2014) A Drosophila model of mitochondrial disease caused by a complex I mutation that uncouples proton pumping from electron transfer. Dis Model Mech 7:1165-74 |
