Work

Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation

Year: 2024

Type: article

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. High mitochondrial DNA content is reported to be beneficial for health. However here, Landoni et al. show that boosting mtDNA replication disrupts cardiac maturation and induces the mitochondrial integrated stress response, ferroptosis and neonatal heart failure.

Source: Nature Communications

DOI: 10.1038/s41467-024-52164-1