Mitochondrial behaviors prime the selective inheritance against harmful mitochondrial DNA mutations

https://www.biorxiv.org/content/biorxiv/early/2019/05/24/646638.full.pdf

Zhe Chen, Zong-Heng Wang, Guofeng Zhang and Hong Xu

• The authors investigate the mechanism of selective inheritance of a deleterious temperature-sensitive mitochondrial DNA mutation in the germline of Drosophila. At 29C, this allele is selected against.
• They show that mitochondria become fragmented such that >90% of organelles contain a single mitochondrial nucleoid in the germarium 2A region of developing Drosophila ovaries. Nucleoids were found to contain 1.3 mtDNAs on average, suggesting that intra-nucleoid complementation is limited.
• Inhibition of fission caused the inter-generational selection against the mutation to essentially be eliminated. 
• They show that in region 2B, mitochondrial transcripts are expressed (shown via fluoresence in-situ hybridization), and the TMRM:MitoTracker ratio is increased by ~x3 fold.
• Knock-down of cox5A resulted in diminished selection, suggesting that activation of mitochondrial respiration is necessary for selection. Similarly, expression of AOX, which by-passes the electron transport chain, resulted in diminished selection. Also, inhibition of mtDNA replication diminished selection (although mean heteroplasmy was also lower in the control setting, at the permissive temperature of 18C, in this case).
• To summarise, the authors demonstrate that mitochondrial fission, combined with a suppression of mtDNA replication, in proliferating germ cells segregates mtDNA into individual organelles. The expression of mtDNA induces a genotype-phenotype correspondence for individual organelles, whereby defective organelles are removed and consequently an elimination of mutated molecules of mtDNA.