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Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation

Author

Listed:
  • Juan C. Landoni

    (University of Helsinki)

  • Semin Erkul

    (University of Helsinki)

  • Tuomas Laalo

    (University of Helsinki)

  • Steffi Goffart

    (University of Eastern Finland)

  • Riikka Kivelä

    (University of Helsinki
    Wihuri Research Institute
    University of Jyväskylä)

  • Karlo Skube

    (University of Helsinki)

  • Anni I. Nieminen

    (University of Helsinki)

  • Sara A. Wickström

    (University of Helsinki
    Wihuri Research Institute)

  • James Stewart

    (Newcastle University)

  • Anu Suomalainen

    (University of Helsinki
    Helsinki University Hospital
    University of Helsinki)

Abstract

High mitochondrial DNA (mtDNA) amount has been reported to be beneficial for resistance and recovery of metabolic stress, while increased mtDNA synthesis activity can drive aging signs. The intriguing contrast of these two mtDNA boosting outcomes prompted us to jointly elevate mtDNA amount and frequency of replication in mice. We report that high activity of mtDNA synthesis inhibits perinatal metabolic maturation of the heart. The offspring of the asymptomatic parental lines are born healthy but manifest dilated cardiomyopathy and cardiac collapse during the first days of life. The pathogenesis, further enhanced by mtDNA mutagenesis, involves prenatal upregulation of mitochondrial integrated stress response and the ferroptosis-inducer MESH1, leading to cardiac fibrosis and cardiomyocyte death after birth. Our evidence indicates that the tight control of mtDNA replication is critical for early cardiac homeostasis. Importantly, ferroptosis sensitivity is a potential targetable mechanism for infantile-onset cardiomyopathy, a common manifestation of mitochondrial diseases.

Suggested Citation

  • Juan C. Landoni & Semin Erkul & Tuomas Laalo & Steffi Goffart & Riikka Kivelä & Karlo Skube & Anni I. Nieminen & Sara A. Wickström & James Stewart & Anu Suomalainen, 2024. "Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52164-1
    DOI: 10.1038/s41467-024-52164-1
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    References listed on IDEAS

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    1. Aleksandra Trifunovic & Anna Wredenberg & Maria Falkenberg & Johannes N. Spelbrink & Anja T. Rovio & Carl E. Bruder & Mohammad Bohlooly-Y & Sebastian Gidlöf & Anders Oldfors & Rolf Wibom & Jan Törnell, 2004. "Premature ageing in mice expressing defective mitochondrial DNA polymerase," Nature, Nature, vol. 429(6990), pages 417-423, May.
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