Mitochondrial fragmentation drives selective removal of deleterious mtDNA in the germline

• Published in: Nature (London) 2019-06, Vol.570 (7761), p.380-384
• Main Authors: Lieber, Toby, Jeedigunta, Swathi P., Palozzi, Jonathan M., Lehmann, Ruth, Hurd, Thomas R.
• Format: Article
• Language: English
• Subjects: 13; 13/89; 14; 14/19; 14/32; 631/136/2434/1706; 631/80/642/333; 631/80/642/333/1465; 64; 64/24; 82; 82/1; 82/51; Adenosine Triphosphate - metabolism; Animals; Apoptosis; Autophagy-Related Protein-1 Homolog - metabolism; BNIP3 protein; Complementation; Cysts; Cytochrome; Deoxyribonucleic acid; Development strategies; DNA; DNA sequencing; DNA, Mitochondrial - genetics; DNA, Mitochondrial - isolation & purification; Drosophila; Drosophila - cytology; Drosophila - genetics; Drosophila melanogaster - cytology; Drosophila melanogaster - genetics; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Female; Fluorescence; Fragmentation; Fusion protein; Genomes; Germ Cells - metabolism; Humanities and Social Sciences; Hybridization; Insects; Letter; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Methods; Mitochondria; Mitochondria - genetics; Mitochondrial DNA; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mitophagy; Molecular modelling; Morphology; multidisciplinary; Mutation; Mutation rates; Nucleotide sequencing; Oogenesis; Phosphorylation; Physiological aspects; Proteins; Recombination; Reduction; Science; Science (multidisciplinary); Stem cells
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1213-4

Mitochondria contain their own genomes that, unlike nuclear genomes, are inherited only in the maternal line. Owing to a high mutation rate and low levels of recombination of mitrochondrial DNA (mtDNA), special selection mechanisms exist in the female germline to prevent the accumulation of deleterious mutations 1 – 5 . However, the molecular mechanisms that underpin selection are poorly understood 6 . Here we visualize germline selection in Drosophila using an allele-specific fluorescent in situ-hybridization approach to distinguish wild-type from mutant mtDNA. Selection first manifests in the early stages of Drosophila oogenesis, triggered by reduction of the pro-fusion protein Mitofusin. This leads to the physical separation of mitochondrial genomes into different mitochondrial fragments, which prevents the mixing of genomes and their products and thereby reduces complementation. Once fragmented, mitochondria that contain mutant genomes are less able to produce ATP, which marks them for selection through a process that requires the mitophagy proteins Atg1 and BNIP3. A reduction in Atg1 or BNIP3 decreases the amount of wild-type mtDNA, which suggests a link between mitochondrial turnover and mtDNA replication. Fragmentation is not only necessary for selection in germline tissues, but is also sufficient to induce selection in somatic tissues in which selection is normally absent. We postulate that there is a generalizable mechanism for selection against deleterious mtDNA mutations, which may enable the development of strategies for the treatment of mtDNA disorders. An in situ hybridization approach is used to visualize mitochondrial DNA germline selection in Drosophila , revealing the role of mitochondrial fragmentation in the selection against deleterious mutations.