Your browser doesn't support javascript.
loading
Critical contribution of mitochondria in the development of cardiomyopathy linked to desmin mutation.
Hovhannisyan, Yeranuhi; Li, Zhenlin; Callon, Domitille; Suspène, Rodolphe; Batoumeni, Vivien; Canette, Alexis; Blanc, Jocelyne; Hocini, Hakim; Lefebvre, Cécile; El-Jahrani, Nora; Kitsara, Maria; L'honoré, Aurore; Kordeli, Ekaterini; Fornes, Paul; Concordet, Jean-Paul; Tachdjian, Gérard; Rodriguez, Anne-Marie; Vartanian, Jean-Pierre; Béhin, Anthony; Wahbi, Karim; Joanne, Pierre; Agbulut, Onnik.
Afiliación
  • Hovhannisyan Y; UMR CNRS 8256, INSERM U1164, Biological Adaptation and Ageing, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 7, Quai St Bernard (case 256), 75005, Paris, France.
  • Li Z; UMR CNRS 8256, INSERM U1164, Biological Adaptation and Ageing, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 7, Quai St Bernard (case 256), 75005, Paris, France.
  • Callon D; UMR CNRS 8256, INSERM U1164, Biological Adaptation and Ageing, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 7, Quai St Bernard (case 256), 75005, Paris, France.
  • Suspène R; Department of Pathology, Academic Hospital of Reims, Reims, France.
  • Batoumeni V; Virus and Cellular Stress Unit, Department of Virology, Institut Pasteur, Université Paris Cité, Paris, France.
  • Canette A; UMR CNRS 8256, INSERM U1164, Biological Adaptation and Ageing, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 7, Quai St Bernard (case 256), 75005, Paris, France.
  • Blanc J; Ksilink, Strasbourg, France.
  • Hocini H; Service de Microscopie Électronique (IBPS-SME), Institut de Biologie Paris-Seine (IBPS), CNRS, Sorbonne Université, Paris, France.
  • Lefebvre C; UMR CNRS 8256, INSERM U1164, Biological Adaptation and Ageing, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 7, Quai St Bernard (case 256), 75005, Paris, France.
  • El-Jahrani N; INSERM U955, Equipe 16, Université Paris-Est Créteil, Créteil, France.
  • Kitsara M; INSERM U955, Equipe 16, Université Paris-Est Créteil, Créteil, France.
  • L'honoré A; INSERM U955, Equipe 16, Université Paris-Est Créteil, Créteil, France.
  • Kordeli E; UMR CNRS 8256, INSERM U1164, Biological Adaptation and Ageing, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 7, Quai St Bernard (case 256), 75005, Paris, France.
  • Fornes P; UMR CNRS 8256, INSERM U1164, Biological Adaptation and Ageing, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 7, Quai St Bernard (case 256), 75005, Paris, France.
  • Concordet JP; UMR CNRS 8256, INSERM U1164, Biological Adaptation and Ageing, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 7, Quai St Bernard (case 256), 75005, Paris, France.
  • Tachdjian G; Department of Pathology, Academic Hospital of Reims, Reims, France.
  • Rodriguez AM; INSERM U1154, CNRS UMR7196, Museum National d'Histoire Naturelle, Paris, France.
  • Vartanian JP; Laboratoire de Cytogénétique, Service d'Histologie-Embryologie-Cytogénétique, AP-HP, Hôpital Antoine Béclère, Université Paris Saclay, Clamart, France.
  • Béhin A; UMR CNRS 8256, INSERM U1164, Biological Adaptation and Ageing, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 7, Quai St Bernard (case 256), 75005, Paris, France.
  • Wahbi K; Virus and Cellular Stress Unit, Department of Virology, Institut Pasteur, Université Paris Cité, Paris, France.
  • Joanne P; Reference Center for Muscle Diseases Paris-Est, Myology Institute, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne Université, Paris, France.
  • Agbulut O; Cardiology Department, AP-HP, Cochin Hospital, Université Paris Cité, Paris, France.
Stem Cell Res Ther ; 15(1): 10, 2024 01 02.
Article en En | MEDLINE | ID: mdl-38167524
ABSTRACT

BACKGROUND:

Beyond the observed alterations in cellular structure and mitochondria, the mechanisms linking rare genetic mutations to the development of heart failure in patients affected by desmin mutations remain unclear due in part, to the lack of relevant human cardiomyocyte models.

METHODS:

To shed light on the role of mitochondria in these mechanisms, we investigated cardiomyocytes derived from human induced pluripotent stem cells carrying the heterozygous DESE439K mutation that were either isolated from a patient or generated by gene editing. To increase physiological relevance, cardiomyocytes were either cultured on an anisotropic micropatterned surface to obtain elongated and aligned cardiomyocytes, or as a cardiac spheroid to create a micro-tissue. Moreover, when applicable, results from cardiomyocytes were confirmed with heart biopsies of suddenly died patient of the same family harboring DESE439K mutation, and post-mortem heart samples from five control healthy donors.

RESULTS:

The heterozygous DESE439K mutation leads to dramatic changes in the overall cytoarchitecture of cardiomyocytes, including cell size and morphology. Most importantly, mutant cardiomyocytes display altered mitochondrial architecture, mitochondrial respiratory capacity and metabolic activity reminiscent of defects observed in patient's heart tissue. Finally, to challenge the pathological mechanism, we transferred normal mitochondria inside the mutant cardiomyocytes and demonstrated that this treatment was able to restore mitochondrial and contractile functions of cardiomyocytes.

CONCLUSIONS:

This work highlights the deleterious effects of DESE439K mutation, demonstrates the crucial role of mitochondrial abnormalities in the pathophysiology of desmin-related cardiomyopathy, and opens up new potential therapeutic perspectives for this disease.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Pluripotentes Inducidas / Cardiomiopatías Límite: Humans Idioma: En Revista: Stem Cell Res Ther Año: 2024 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Pluripotentes Inducidas / Cardiomiopatías Límite: Humans Idioma: En Revista: Stem Cell Res Ther Año: 2024 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Reino Unido