PT  - JOURNAL ARTICLE
AU  - Zhe Chen
AU  - Zong-Heng Wang
AU  - Guofeng Zhang
AU  - Christopher K. E. Bleck
AU  - Dillon J. Chung
AU  - Grey Madison
AU  - Eric Lindberg
AU  - Christian Combs
AU  - Robert S. Balaban
AU  - Hong Xu
TI  - Developmentally-orchestrated mitochondrial processes prime the selective inheritance against harmful mitochondrial DNA mutations
AID  - 10.1101/646638
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 646638
4099  - http://biorxiv.org/content/early/2019/11/19/646638.short
4100  - http://biorxiv.org/content/early/2019/11/19/646638.full
AB  - Although mitochondrial DNA (mtDNA) is prone to mutation and not all conventional DNA repair systems operate in mitochondria, deleterious mutations are exceedingly rare. How the transmission of detrimental mtDNA mutations is 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 processes. We demonstrate that mitochondrial fission, together with the lack of mtDNA replication in germarium region 2A, effectively segregates mtDNA into individual organelles. After mtDNA segregation, mtDNA transcription begins, which leads to the activation of respiration in each organelle. The expression of mtDNA-encoded genes 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.