Mitochondrial Fragmentation Drives the Selective Removal of Deleterious Mitochondrial DNA in the Drosophila Germline T. Hurd1, T. Lieber2, R. Lehmann2 1Department of Molecular Genetics, University of Toronto; 2Skirball Institute, NYU School of Medicine
Mitochondria are unusual among animal organelles in that they contain their own genomes. Unlike nuclear genomes, mitochondrial genomes are inherited only maternally, are subject to a high mutation rate and undergo little recombination. Therefore, if left alone deleterious mutations would accumulate from one generation to the next. However, special selection mechanisms exist in the female germline to prevent this accumulation. Remarkably, despite its fundamental scientific and medical importance, the molecular mechanisms underpinning mtDNA selection remain poorly understood. Here, using an allele-specific fluorescent in situ hybridization approach to distinguish wildtype from mutant mtDNA, we have visualized germline mtDNA selection for the first time. Selection first manifests in the early stages of Drosophila oogenesis, specifically in differentiating germline cysts. We find that just prior, there is a dramatic decrease in mitochondrial fusion, induced by a reduction in the levels of the pro-fusion protein Mitofusin (also known as Marf in Drosophila). We show that the resulting fragmented phase is necessary to isolate mitochondria and prevent them from sharing their contents, which in turn reduces product complementation and allows mitochondria harboring mutant genomes to be selected against. Remarkably, not only is this prolonged fragmented phase necessary for selection in germline tissues, but promoting fragmentation is also sufficient to induce selection in somatic ovarian tissues where selection otherwise does not appreciably occur. Our results demonstrate that the key distinction underlying the female germline's capacity to select against deleterious mitochondria is a developmentally regulated period of isolation that germline mitochondria undergo during early oogenesis. Mutations in mtDNA are increasingly being recognized as a major cause of human disease. Understanding how the germline isolates mitochondria to select against deleterious mtDNA mutations may allow for the development of somatic therapies to treat those suffering from mtDNA disorders.
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