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Mitochondrial fragmentation drives selective removal of deleterious mtDNA in the germline

Author

Listed:
  • Toby Lieber

    (New York University School of Medicine)

  • Swathi P. Jeedigunta

    (University of Toronto)

  • Jonathan M. Palozzi

    (University of Toronto)

  • Ruth Lehmann

    (New York University School of Medicine)

  • Thomas R. Hurd

    (University of Toronto)

Abstract

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 mutations1–5. However, the molecular mechanisms that underpin selection are poorly understood6. 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.

Suggested Citation

  • Toby Lieber & Swathi P. Jeedigunta & Jonathan M. Palozzi & Ruth Lehmann & Thomas R. Hurd, 2019. "Mitochondrial fragmentation drives selective removal of deleterious mtDNA in the germline," Nature, Nature, vol. 570(7761), pages 380-384, June.
  • Handle: RePEc:nat:nature:v:570:y:2019:i:7761:d:10.1038_s41586-019-1213-4
    DOI: 10.1038/s41586-019-1213-4
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    Cited by:

    1. Sunjoo Joo & Thamali Kariyawasam & Minjae Kim & EonSeon Jin & Ursula Goodenough & Jae-Hyeok Lee, 2022. "Sex-linked deubiquitinase establishes uniparental transmission of chloroplast DNA," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Annabel Qi En Ng & Seow Neng Chan & Jun Wei Pek, 2024. "Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Jack Holcombe & Helen Weavers, 2023. "Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Bryan L. Gitschlag & Claudia V. Pereira & James P. Held & David M. McCandlish & Maulik R. Patel, 2024. "Multiple distinct evolutionary mechanisms govern the dynamics of selfish mitochondrial genomes in Caenorhabditis elegans," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Patricia Rojas-Ríos & Aymeric Chartier & Camille Enjolras & Julie Cremaschi & Céline Garret & Adel Boughlita & Anne Ramat & Martine Simonelig, 2024. "piRNAs are regulators of metabolic reprogramming in stem cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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