Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation
Landoni, J. C., Erkul, S., Laalo, T., Goffart, S., Kivelä, R., Skube, K., Nieminen, A. I., Wickström, S. A., Stewart, J., & Suomalainen, A. (2024). Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation. Nature Communications, 15, Article 8066. https://doi.org/10.1038/s41467-024-52164-1
Julkaistu sarjassa
Nature CommunicationsTekijät
Päivämäärä
2024Tekijänoikeudet
© The Author(s) 2024
2024:23 | 2025:8
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.
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Springer NatureISSN Hae Julkaisufoorumista
2041-1723Asiasanat
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https://converis.jyu.fi/converis/portal/detail/Publication/243041514
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This work was supported by the following funders (recipient initials in parentheses): Sigrid Jusélius Foundation (AS, RK), Research Council of Finland (AS [361873, 345248], RK [297245]), Helsinki University Hospital (AS), Max Planck Society (JS), Finnish Foundation for Cardiovascular Research (RK), University of Helsinki Funds (JCL), Maud Kuistila Foundation (JCL), Päivikki ja Sakari Sohlberg Foundation (JCL), and the Biomedicum Helsinki Foundation (JCL). ...Lisenssi
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