Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis

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

Feng Li; Yunyue Wang; Karen I. Zeller; James J. Potter; Diane R. Wonsey; Kathryn A. O'Donnell; Jung-whan Kim; Jason T. Yustein; Linda A. Lee; Chi V. Dang

2005

Scholarcy highlights

  • MYC, which encodes a transcription factor, c-Myc, plays a central role in the regulation of cell size, cell proliferation, and apoptosis through its regulation of RNA polymerase I, II, and III-dependent 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
  • Did we observe that mitochondrial biogenesis depends on Myc, but we found that among the Myc target genes most highly induced in the human B-cell system are those involved in mitochondrial biogenesis
  • Flow cytometry using NAO, whose staining of mitochondrial cardiolipin gives a measure of mitochondrial mass, revealed that Myc induction increases mitochondrial mass, the induction is blunted in the absence of serum
  • To further substantiate these findings, we measured mitochondrial DNA content by using real-time quantitative PCR and cellular oxygen consumption as indicators of mitochondrial mass and function, respectively. Both mitochondrial DNA and cellular oxygen consumption increased with Myc induction in the P493-6 B cells. These observations support the notion that Myc induces mitochondrial biogenesis; whether Myc is necessary for mitochondrial biogenesis could not be discerned in the P493-6 system
  • We provide evidence both by in vitro and in vivo ectopic expression of Myc and by studying Myc null fibroblasts and acute deletion of floxed murine Myc in primary hepatocytes that Myc affects mitochondrial biogenesis, presumably through its direct regulation of genes involved in mitochondrial biogenesis
  • Our findings demonstrate a role for Myc in regulating genes involved in mitochondrial structure and function and in mitochondrial biogenesis and further establish that Myc is a master switch that couples cellular metabolic needs to cell growth and proliferation

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