Mitochondrial behaviors prime the selective inheritance against harmful mitochondrial DNA mutations

Although mitochondrial DNA (mtDNA) is prone to mutation and few mtDNA repair mechanisms exist, deleterious mutations are exceedingly rare. How the transmission of detrimental mtDNA mutations are restricted through the maternal lineage is debated. Here, we use Drosophila to dissect the mechanisms of mtDNA selective inheritance and understand their molecular underpinnings. Our observations support a purifying selection at the organelle level based on a series of developmentally-orchestrated mitochondrial behaviors. We demonstrate that mitochondrial fission, together with the lack of mtDNA replication in proliferating germ cells, effectively segregates mtDNA into individual organelles. After mtDNA segregation, mtDNA expression begins, which leads to the activation of respiration in each organelle. The expression of mtDNA allows the functional manifestation of different mitochondrial genotypes in heteroplasmic cells, and hence functions as a stress test for each individual genome and sets the stage for the replication competition. We also show that the Balbiani body has a minor role in mtDNA selective inheritance by supplying healthy mitochondria to the pole plasm. The two selection mechanisms may act synergistically to secure the transmission of functional mtDNA through Drosophila oogenesis.