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Molecular and Cellular Biology, September 2007, p. 6420-6432, Vol. 27, No. 18
0270-7306/07/$08.00+0     doi:10.1128/MCB.01946-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Mitochondrial Respiratory Chain Controls Intracellular Calcium Signaling and NFAT Activity Essential for Heart Formation in Xenopus laevis{triangledown} ,{dagger}

Yong Chen,1 Wai Hong Yuen,2 Jianlin Fu,2 Guochang Huang,2,{ddagger} Alirio J. Melendez,3 Farazeela Bte Mohod Ibrahim,3 Hao Lu,1 and Xinmin Cao1*

Signal Transduction Laboratory, Institute of Molecular and Cell Biology,1 Transgenic Frog Facility, Institute of Molecular and Cell Biology,2 Molecular and Cell Immunology Laboratory, Department of Physiology, National University of Singapore, Singapore, Republic of Singapore3

Received 16 October 2006/ Returned for modification 14 December 2006/ Accepted 29 June 2007

The mitochondrial respiratory chain (MRC) plays crucial roles in cellular energy production. However, its function in early embryonic development remains largely unknown. To address this issue, GRIM-19, a newly identified MRC complex I subunit, was knocked down in Xenopus laevis embryos. A severe deficiency in heart formation was observed, and the deficiency could be rescued by reintroducing human GRIM-19 mRNA. The mechanism involved was further investigated. We found that the activity of NFAT, a transcription factor family that contributes to early organ development, was downregulated in GRIM-19 knockdown embryos. Furthermore, the expression of a constitutively active form of mouse NFATc4 in these embryos rescued the heart developmental defects. NFAT activity is controlled by a calcium-dependent protein phosphatase, calcineurin, which suggests that calcium signaling may be disrupted by GRIM-19 knockdown. Indeed, both the calcium response and calcium-induced NFAT activity were impaired in the GRIM-19 or NDUFS3 (another complex I subunit) knockdown cell lines. We also showed that NFAT can rescue expression of Nkx2.5, which is one of the key genes for early heart development. Our data demonstrated the essential role of MRC in heart formation and revealed the signal transduction and gene expression cascade involved in this process.

* Corresponding author. Mailing address: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Republic of Singapore. Phone: 65-65869657. Fax: 65-67791117. E-mail: mcbcaoxm{at}imcb.a-star.edu.sg

{triangledown} Published ahead of print on 16 July 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

Molecular and Cellular Biology, September 2007, p. 6420-6432, Vol. 27, No. 18
0270-7306/07/$08.00+0     doi:10.1128/MCB.01946-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kim, M.-S., Usachev, Y. M. (2009). Mitochondrial Ca2+ Cycling Facilitates Activation of the Transcription Factor NFAT in Sensory Neurons. J. Neurosci. 29: 12101-12114 [Abstract] [Full Text]  
  • Lu, H., Cao, X. (2008). GRIM-19 Is Essential for Maintenance of Mitochondrial Membrane Potential. Mol. Biol. Cell 19: 1893-1902 [Abstract] [Full Text]  


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