Mitochondrial Fusion Directs Cardiomyocyte Differentiation via Calcineurin and Notch Signaling

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Science  08 Nov 2013:
Vol. 342, Issue 6159, pp. 734-737
DOI: 10.1126/science.1241359

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Mitochondrial Fusion and Heart Development

The role of mitochondria in fueling homeostatic cell processes is well appreciated, but whether and how they influence cell differentiation is much less clear. Using in vivo embryonic mouse models and mouse embryonic stem cell cultures, Kasahara et al. (p. 734, published online 3 October) found that an intact mitochondrial fusion pathway was essential for the cellular signaling that drives mesodermal cell differentiation into cardiomyocytes.


Mitochondrial morphology is crucial for tissue homeostasis, but its role in cell differentiation is unclear. We found that mitochondrial fusion was required for proper cardiomyocyte development. Ablation of mitochondrial fusion proteins Mitofusin 1 and 2 in the embryonic mouse heart, or gene-trapping of Mitofusin 2 or Optic atrophy 1 in mouse embryonic stem cells (ESCs), arrested mouse heart development and impaired differentiation of ESCs into cardiomyocytes. Gene expression profiling revealed decreased levels of transcription factors transforming growth factor–β/bone morphogenetic protein, serum response factor, GATA4, and myocyte enhancer factor 2, linked to increased Ca2+-dependent calcineurin activity and Notch1 signaling that impaired ESC differentiation. Orchestration of cardiomyocyte differentiation by mitochondrial morphology reveals how mitochondria, Ca2+, and calcineurin interact to regulate Notch1 signaling.

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