Developmentally-orchestrated mitochondrial processes prime the selection against harmful mtDNA mutations

February 13, 2020

Zhe Chen (1), Zong-Heng Wang (1), Guofeng Zhang (2), Christopher K. E. Bleck (1), Dillon J. Chung (1), Grey Madison (1), Eric Lindberg (1), Christian Combs (1), Robert S. Balaban (1), Hong Xu (1)
bioRxiv, February 2020. DOI: 10.1101/646638


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 early germarium, 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.

How Our Software Was Used

Dragonfly was used to segment the mitochondria and cells, and to collect mitochondrial morphometric information.

Author Affiliation

(1) National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
(2) National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892.