Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation

Juan C. Landoni (), Semin Erkul, Tuomas Laalo, Steffi Goffart, Riikka Kivelä, Karlo Skube, Anni I. Nieminen, Sara A. Wickström, James Stewart and Anu Suomalainen ()
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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
Karlo Skube: University of Helsinki
Anni I. Nieminen: University of Helsinki
Sara A. Wickström: University of Helsinki
James Stewart: Newcastle University
Anu Suomalainen: University of Helsinki

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52164-1

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