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Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation.
Landoni, Juan C; Erkul, Semin; Laalo, Tuomas; Goffart, Steffi; Kivelä, Riikka; Skube, Karlo; Nieminen, Anni I; Wickström, Sara A; Stewart, James; Suomalainen, Anu.
Afiliación
  • Landoni JC; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. juan.landoni@epfl.ch.
  • Erkul S; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Laalo T; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Goffart S; Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland.
  • Kivelä R; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Skube K; Wihuri Research Institute, Helsinki, Finland.
  • Nieminen AI; Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
  • Wickström SA; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Stewart J; Metabolomics Unit, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Suomalainen A; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Nat Commun ; 15(1): 8066, 2024 Sep 14.
Article en En | MEDLINE | ID: mdl-39277581
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN Mitocondrial / Miocitos Cardíacos / Replicación del ADN Límite: Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN Mitocondrial / Miocitos Cardíacos / Replicación del ADN Límite: Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Reino Unido