Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis

Abstract

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.

SUPPLEMENTAL MATERIAL

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

ACKNOWLEDGMENTS

We thank D. Eick for P493-6 cells, J. Sedivy for TGR and HO15 cells, and P. Puigserver for comments on the manuscript. We thank D. Murphy for kind instruction on sample preparation and data analysis for confocal microscopy and electron microscopy, Y. Ko for technical assistance with the stimulated cellular oxygen consumption assay, and L. Blosser for the flow cytometry assay. We thank Francisco Martinez Murillo and Chunfa Jie for microarray hybridization and data analysis.

This work was supported by NIH/NCI grants CA52497, CA57341, and CA09159 and the Training Program in Human Genetics and Molecular Biology. J. Kim is a Howard Hughes Medical Institute predoctoral fellow. C. Dang is the Johns Hopkins Family Professor in Oncology Research.