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Molecular and Cellular Biology, July 2005, p. 6225-6234, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.6225-6234.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis{dagger}

Feng Li,1* Yunyue Wang,1 Karen I. Zeller,1 James J. Potter,2 Diane R. Wonsey,1,{ddagger} Kathryn A. O'Donnell,3 Jung-whan Kim,4 Jason T. Yustein,5 Linda A. Lee,2 and Chi V. Dang1,3,4,6*

Divisions of Hematology,1 Gastroenterology, Department of Medicine,2 Department of Cell Biology,6 Graduate Programs in Human Genetics and Molecular Biology,3 Pathobiology,4 Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland5

Received 12 January 2005/ Returned for modification 22 February 2005/ Accepted 11 April 2005

Although several genes involved in mitochondrial function are direct Myc targets, the role of Myc in mitochondrial biogenesis has not been directly established. We determined the effects of ectopic Myc expression or the loss of Myc on mitochondrial biogenesis. Induction of Myc in P493-6 cells resulted in increased oxygen consumption and mitochondrial mass and function. Conversely, compared to wild-type Myc fibroblasts, Myc null rat fibroblasts have diminished mitochondrial mass and decreased number of normal mitochondria. Reconstitution of Myc expression in Myc null fibroblasts partially restored mitochondrial mass and function and normal-appearing mitochondria. Concordantly, we also observed in primary hepatocytes that acute deletion of floxed murine Myc by Cre recombinase resulted in diminished mitochondrial mass in primary hepatocytes. Our microarray analysis of genes responsive to Myc in human P493-6 B lymphocytes supports a role for Myc in mitochondrial biogenesis, since genes involved in mitochondrial structure and function are overrepresented among the Myc-induced genes. In addition to the known direct binding of Myc to many genes involved in mitochondrial structure and function, we found that Myc binds the TFAM gene, which encodes a key transcriptional regulator and mitochondrial DNA replication factor, both in P493-6 lymphocytes with high ectopic MYC expression and in serum-stimulated primary human 2091 fibroblasts with induced endogenous MYC. These observations support a pivotal role for Myc in regulating mitochondrial biogenesis.

* Corresponding author. Mailing address: Ross Building, Room 1032, 720 Rutland Avenue, Baltimore, MD 21205. Phone: (410) 955-2773. Fax: (410) 955-0185. E-mail for Chi V. Dang: cvdang{at}jhmi.edu. E-mail for Feng Li: fli3{at}jhmi.edu.

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

{ddagger} Present address: 200 Cambridge Park Drive, Cambridge, MA 02140.

Molecular and Cellular Biology, July 2005, p. 6225-6234, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.6225-6234.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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