Regulation of mitochondrial heteroplasmy dynamics

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PROJECT SUMMARY/ABSTRACT Mitochondrial dysfunction is a major cellular hallmark of many inherited diseases, as well as age-dependent degenerative disorders. Mutations in the mitochondrial genome (mtDNA), which encodes essential components of the electron transport chain, are a common cause of mitochondrial diseases. Mutant mtDNA copies are frequently co-inherited with wildtype mtDNA in a state of heteroplasmy, and become pathogenic when their levels reach a critical threshold. Consequently, a central challenge is to understand the processes that regulate transmission of heteroplasmic mutations through the female germline, and their accumulation in somatic tissues during aging. Traditionally, studies of mtDNA heteroplasmy dynamics have been hampered by the need to track heteroplasmy levels across multiple generations, and to do so in a quantitatively rigorous manner. We have adapted key technological innovations, and have developed Caenorhabditis species of nematodes as genetically tractable metazoan model systems, to overcome these limitations. We are now poised to shed light on mechanisms that regulate heteroplasmy dynamics. In aim 1, we will determine the molecular basis of mtDNA copy number control, which we have discovered is an important determinant of inherited mutant mtDNA levels. We will do so by using a large collection of heteroplasmic strains that we have identified from a whole genome sequencing project in C. elegans. In aim 2, we will test the hypothesis that by allowing cells to tolerate mitochondrial dysfunction, homeostatic stress responses inadvertently allow mutant mtDNA to rise to pathogenically high levels. We will do so by determining the mechanisms that function downstream of the mitochondrial unfolded protein response, which we recently reported protects mutant mtDNA from mitophagy. In aim 3, we will generate heteroplasmies consisting of wildtype mtDNA haplotypes from two different species of nematodes. We will cross these into different nuclear backgrounds and assess if there is biased mtDNA transmission to determine the role of the nuclear genome in regulating heteroplasmy dynamics. Taken together, this research proposal will shed fundamental light on the cellular and molecular mechanisms that regulate heteroplasmy dynamics. A better understanding of these mechanisms will make it possible to predict and potentially develop therapeutics to prevent transmission of pathogenic mtDNA mutations.