Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation
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.
Authors
- James B. Stewart (ORCID: https://orcid.org/0000-0002-2902-4968)
- Anni I. Nieminen (ORCID: https://orcid.org/0000-0001-8999-6040)
- Riikka Kivelä (ORCID: https://orcid.org/0000-0002-2686-8890)
- Sara A. Wickström (ORCID: https://orcid.org/0000-0001-6383-6292)
- Anu Suomalainen (ORCID: https://orcid.org/0000-0003-4833-5195)
- Tuomas Laalo (ORCID: https://orcid.org/0000-0001-5419-0856)
- Karlo Skube (ORCID: https://orcid.org/0000-0002-6797-0584)
- Steffi Goffart (ORCID: https://orcid.org/0000-0001-8491-1458)
- Juan C. Landoni (ORCID: https://orcid.org/0000-0002-0318-6707)
- Semin Erkul (ORCID: https://orcid.org/0000-0001-7422-9885)
Institutions
- University of Helsinki (FI)
- University of Eastern Finland (FI)
- Helsinki University Hospital (FI)
- Wihuri Research Institute (FI)
- Institute for Molecular Medicine Finland (FI)
- Hospital District of Helsinki and Uusimaa (FI)
- Newcastle University (GB)
- University of Jyväskylä (FI)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-14
- DOI
- https://doi.org/10.1038/s41467-024-52164-1
- Citations
- 8
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- Foundation for Cardiovascular Research
- Helsingin Yliopisto
- Maud Kuistilan Muistosäätiö
- Academy of Finland
- Biomedicum Helsinki-säätiö
- Max-Planck-Gesellschaft
- Päivikki ja Sakari Sohlbergin Säätiö
- Sydäntutkimussäätiö
- Sigrid Juséliuksen Säätiö
- Biocenter Finland
- Helsinki Institute of Life Science, Helsingin Yliopisto