Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Clinical Practice Cardiovascular Medicine volume 4, pages S60–S67 (2007)Cite this article

Abstract

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.

Key Points

  • While anaerobic metabolism is sufficient to sustain embryonic stem cell energetics, it must be transformed into mitochondria-mediated oxidative metabolism to secure cardiac specification

  • Induction of cardiogenic pathways is linked to restructuring of the metabolic transcriptome and organization of the mitochondrial network

  • Maturation and integration of mitochondria with the nascent electromechanical apparatus confer the functional competence required to develop a cardiac phenotype

  • Disruption of respiratory chain function and prevention of mitochondrial network organization compromise the developing energetic infrastructure, causing deficient sarcomere formation, improper beating area assembly, and defective contractility

  • As mandatory components of genomic reprogramming during cardiac differentiation, energetic circuits are metabolic regulators of cardiogenesis and targets for heart regeneration

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Embryonic stem cell cardiac differentiation is coordinated with metabolic transcriptome reprogramming and mitochondrial oxidative metabolism
Figure 2: Development and maturation of mitochondrial network in stem cell cardiac differentiation
Figure 3: Disturbed execution of the cardiac differentiation program with inhibition of the mitochondrial respiratory chain

Similar content being viewed by others

References

  1. Donovan PJ and Gearhart J (2001) The end of the beginning for pluripotent stem cells. Nature 414: 92–97

    Article  CAS  Google Scholar 

  2. Behfar A et al. (2002) Stem cell differentiation requires a paracrine pathway in the heart. FASEB J 16: 1558–1566

    Article  Google Scholar 

  3. Perez-Terzic C et al. (2003) Structural adaptation of the nuclear pore complex in stem cell-derived cardiomyocytes. Circ Res 92: 444–452

    Article  CAS  Google Scholar 

  4. Hodgson DM et al. (2004) Stable benefit of embryonic stem cell therapy in myocardial infarction. Am J Physiol 287: H471–H479

    CAS  Google Scholar 

  5. Van Laake LW et al. (2005) Cardiomyocytes derived from stem cells. Ann Med 37: 499–512

    Article  CAS  Google Scholar 

  6. Lev S et al. (2005) Differentiation pathways in human embryonic stem cell-derived cardiomyocytes. Ann NY Acad Sci 1047: 50–65

    Article  CAS  Google Scholar 

  7. Kirby ML (2002) Molecular embryogenesis of the heart. Pediatr Dev Pathol 5: 516–543

    Article  Google Scholar 

  8. Foley A and Mercola M (2004) Heart induction: embryology to cardiomyocyte regeneration. Trends Cardiovasc Med 14: 121–125

    Article  CAS  Google Scholar 

  9. Dzeja PP and Terzic A (2003) Phosphotransfer networks and cellular energetics. J Exp Biol 206: 2039–2047

    Article  CAS  Google Scholar 

  10. Naya FJ et al. (2002) Mitochondrial deficiency and cardiac sudden death in mice lacking the MEF2A transcription factor. Nat Med 8: 1303–1309

    Article  CAS  Google Scholar 

  11. Kelly DP and Scarpulla RC (2004) Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 18: 357–368

    Article  CAS  Google Scholar 

  12. Spitkovsky D et al. (2004) Activity of complex III of the mitochondrial electron transport chain is essential for early heart muscle cell differentiation. FASEB J 18: 1300–1302

    Article  CAS  Google Scholar 

  13. St John JC et al. (2005) The expression of mitochondrial DNA transcription factors during early cardiomyocyte in vitro differentiation from human embryonic stem cells. Cloning Stem Cells 7: 141–153

    Article  CAS  Google Scholar 

  14. Behfar A et al. (2005) Administration of allogenic stem cells dosed to secure cardiogenesis and sustained infarct repair. Ann NY Acad Sci 1049: 189–198

    Article  Google Scholar 

  15. Menard C et al. (2005) Transplantation of cardiac-committed mouse embryonic stem cells to infarcted sheep myocardium: a preclinical study. Lancet 366: 1005–1012

    Article  Google Scholar 

  16. Yang Y and Balcarcel RR (2004) 96-well plate assay for sublethal metabolic activity. Assay Drug Dev Technol 2: 353–361

    Article  CAS  Google Scholar 

  17. Dzeja PP et al. (2002) Energetic communication between mitochondria and nucleus directed by catalyzed phosphotransfer. Proc Natl Acad Sci USA 99: 10156–10161

    Article  CAS  Google Scholar 

  18. Perez-Terzic C et al. (2001) Directed inhibition of nuclear import in cellular hypertrophy. J Biol Chem 276: 20566–20571

    Article  CAS  Google Scholar 

  19. Sathananthan H et al. (2002) The fine structure of human embryonic stem cells. Reprod Biomed Online 4: 56–61

    Article  Google Scholar 

  20. Sturmey RG and Leese HJ (2003) Energy metabolism in pig oocytes and early embryos. Reproduction 126: 197–204

    Article  CAS  Google Scholar 

  21. Singla DK et al. (2006) Transplantation of embryonic stem cells into the infarcted mouse heart: formation of multiple cell types. J Mol Cell Cardiol 40: 195–200

    Article  CAS  Google Scholar 

  22. Sathananthan AH and Trounson AO (2000) Mitochondrial morphology during preimplantational human embryogenesis. Hum Reprod 15: 148–159

    Article  Google Scholar 

  23. Goffart S et al. (2004) Regulation of mitochondrial proliferation in the heart: power-plant failure contributes to cardiac failure in hypertrophy. Cardiovasc Res 64: 198–207

    Article  CAS  Google Scholar 

  24. Koyanagi M et al. (2005) Cell-to-cell connection of endothelial progenitor cells with cardiac myocytes by nanotubes: a novel mechanism for cell fate changes? Circ Res 96: 1039–1041

    Article  CAS  Google Scholar 

  25. Smirnova E et al. (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Cell Biol 12: 2245–2256

    Article  CAS  Google Scholar 

  26. Tondera D et al. (2005) The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells. J Cell Sci 118: 3049–3059

    Article  CAS  Google Scholar 

  27. Misaka T et al. (2006) The dynamin-related mouse mitochondrial GTPase OPA1 alters the structure of the mitochondrial inner membrane when exogenously introduced into COS-7 cells. Neurosci Res 55: 123–133

    Article  CAS  Google Scholar 

  28. Mukamel Z and Kimchi A (2004) Death-associated protein 3 localizes to the mitochondria and is involved in the process of mitochondrial fragmentation during cell death. J Biol Chem 279: 36732–36738

    Article  CAS  Google Scholar 

  29. Chen H and Chan DC (2005) Emerging functions of mammalian mitochondrial fusion and fission. Hum Mol Genet 14: R283–R289

    Article  CAS  Google Scholar 

  30. John GB et al. (2005) The mitochondrial inner membrane protein mitofilin controls cristae morphology. Mol Biol Cell 16: 1543–1554

    Article  CAS  Google Scholar 

  31. Seyer P et al. (2006) Mitochondrial activity regulates myoblast differentiation by control of c-Myc expression. J Cell Physiol 207: 75–86

    Article  CAS  Google Scholar 

  32. Smith J et al. (2000) Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc Natl Acad Sci USA 97: 10032–10037

    Article  CAS  Google Scholar 

  33. Sauer H et al. (2000) Role of reactive oxygen species and phosphatidylinositol 3-kinase in cardiomyocyte differentiation of embryonic stem cells. FEBS Lett 476: 218–223

    Article  CAS  Google Scholar 

  34. Noble M et al. (2005) Redox regulation of precursor cell function: insights and paradoxes. Antioxid Redox Signal 7: 1456–1467

    Article  CAS  Google Scholar 

  35. Li J et al. (2006) The NADPH oxidase NOX4 drives cardiac differentiation: Role in regulating cardiac transcription factors and MAP kinase activation. Mol Biol Cell 17: 3978–3988

    Article  CAS  Google Scholar 

  36. Lonergan T et al. (2006) Differentiation-related changes in mitochondrial properties as indicators of stem cell competence. J Cell Physiol 208: 149–153

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institutes of Health (NIH), American Heart Association, Marriott Heart Disease Research Program, Marriott Foundation, Ted Nash Long Life Foundation, Ralph Wilson Medical Research Foundation, Asper Foundation, and the Mayo Clinic Clinician-Investigator Program.

Author information

Authors and Affiliations

  1. Division of Cardiovascular Diseases, S Chung is a Bonner Scholar in Biochemistry and Molecular Biology, PP Dzeja is Assistant Professor of Pharmacology, RS Faustino is Fellow of the Asper Foundation, C Perez-Terzic is Assistant Professor of Physical Medicine and Rehabilitation and Medicine, A Behfar is a Clinician-Investigator Scholar, and A Terzic is Marriott Family Professor of Cardiovascular Research and Professor of Medicine and Pharmacology, Mayo Clinic, Rochester, MN, USA.,

    Susan Chung, Petras P Dzeja, Randolph S Faustino, Carmen Perez-Terzic, Atta Behfar & Andre Terzic

Authors
  1. Susan Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Petras P Dzeja
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Randolph S Faustino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carmen Perez-Terzic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Atta Behfar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andre Terzic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andre Terzic.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chung, S., Dzeja, P., Faustino, R. et al. Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells. Nat Rev Cardiol 4 (Suppl 1), S60–S67 (2007). https://doi.org/10.1038/ncpcardio0766

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpcardio0766

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing