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34 Mitochondrial morphology affects cardiomyocyte differentiation of mouse embryonic stem cells through calcineurin and notch signalling pathways
  1. A Kasahara,
  2. L Scorrano
  1. Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland

Abstract

Mitochondria play essential and versatile roles in cardiomyocyte pathophysiology: they are the main source of ATP; they control apoptosis, and Ca2+ signalling, impacting on almost any process, like outcome of ischaemia/reperfusion and electrical synchronisation during EC coupling. Mounting evidence is supporting a role for mitochondrial shape in determining organellar function. Mitochondrial morphology is controlled by mitochondria-shaping proteins that includes the pro-fusion dynamin-like GTPases optic atrophy 1 (OPA1) and mitofusin (MFN) 1 and 2, and the pro-fission dynamin-related protein 1 and its mitochondrial receptor FIS1. However, if mitochondria-shaping proteins regulate differentiation into functional and specific cell lineages, such as cardiomyocyte, is largely unknown. To understand the role of mitochondria-shaping proteins in cardiomyocyte differentiation, we used mouse ESC lines (Opa1gt and Mfn2gt), which are heterozygous for a gene trap in Opa1 or Mfn2 gene respectively, and performed in vitro differentiation into cardiomyocyte. Downregulation of OPA1 or MFN2 did not affect stemness and self-renewal of ESCs nor mitochondrial bioenergetic parameters, but displayed shorter mitochondria, and abnormal Ca2+ signalling, with sustained capacitative Ca2+ entry, higher calcineurin activity. Hanging-drop differentiation showed that appropriate levels of OPA1 and MFN2 are required for differentiation into cardiomycytes. The differentiation defect was corrected by the calcineurin inhibitor, as well as dominant negative form of calcineurin. Calcineurin in turn triggered higher activity of the inhibitor of cardiomyocyte differentiation Notch. Ablation of OPA1 and MFN2 in ESCs shows that mitochondrial shape regulates cardiomyocyte differentiation by impinging on a pathway involving the phosphatase calcineurin and Notch signalling.

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