Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells

被引:395
作者
Chung S. [1 ]
Dzeja P.P. [2 ]
Faustino R.S. [3 ]
Perez-Terzic C. [4 ]
Behfar A. [5 ]
Terzic A. [5 ]
机构
[1] Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN
[2] Department of Pharmacology, Mayo Clinic, Rochester, MN
[3] Asper Foundation, Mayo Clinic, Rochester, MN
[4] Department of Physical Medicine and Rehabilitation and Medicine, Mayo Clinic, Rochester, MN
[5] Department of Cardiovascular Research, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN
来源
Nature Clinical Practice Cardiovascular Medicine | 2007年 / 4卷 / Suppl 1期
关键词
D O I
10.1038/ncpcardio0766
中图分类号
学科分类号
摘要
Cardiogenesis within embryos or associated with heart repair requires stem cell differentiation into energetically competent, contracting cardiomyocytes. While it is widely accepted that the coordination of genetic circuits with developmental bioenergetics is critical to phenotype specification, the metabolic mechanisms that drive cardiac transformation are largely unknown. Here, we aim to define the energetic requirements for and the metabolic microenvironment needed to support the cardiac differentiation of embryonic stem cells. We demonstrate that anaerobic glycolytic metabolism, while sufficient for embryonic stem cell homeostasis, must be transformed into the more efficient mitochondrial oxidative metabolism to secure cardiac specification and excitation-contraction coupling. This energetic switch was programmed by rearrangement of the metabolic transcriptome that encodes components of glycolysis, fatty acid oxidation, the Krebs cycle, and the electron transport chain. Modifying the copy number of regulators of mitochondrial fusion and fission resulted in mitochondrial maturation and network expansion, which in turn provided an energetic continuum to supply nascent sarcomeres. Disrupting respiratory chain function prevented mitochondrial organization and compromised the energetic infrastructure, causing deficient sarcomerogenesis and contractile malfunction. Thus, establishment of the mitochondrial system and engagement of oxidative metabolism are prerequisites for the differentiation of stem cells into a functional cardiac phenotype. Mitochondria-dependent energetic circuits are thus critical regulators of de novo cardiogenesis and targets for heart regeneration.
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页码:S60 / S67
页数:7
相关论文
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