Sequential serum-dependent activation of CREB and NRF-1 leads to enhanced mitochondrial respiration through the induction of cytochrome c

Ronald P. Herzig, Salvatore Scacco, Richard C. Scarpulla*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

137 Scopus citations

Abstract

Progression thought the cell cycle requires ATP for protein synthesis, cytoskeletal rearrangement, chromatin remodeling, and protein degradation. The mechanisms by which mammalian cells increase respiratory capacity and ATP production in preparation for cell division are largely unexplained. Here, we demonstrate that serum induction of cytochrome c mRNA and processed protein in quiescent BALB/3T3 fibroblasts is associated with a marked increase in mitochondrial respiration. Cytochrome c was induced in the absence of any increase in citrate synthase activity or in subunit IV of the cytochrome c oxidase complex mRNA or protein, indicating that the enhanced respiratory rate did not require a general increase in mitochondrial biogenesis or respiratory chain expression. Transfection with a series of cytochrome c promoter mutants showed that both nuclear respiratory factor I (NRF-1) and cAMP response element-binding protein (CREB) binding sites contributed equally to induced expression by serum. Moreover, CREB and NRF-1 were phosphorylated sequentially in response to serum, and the NRF-1 phosphorylation was accompanied by an increase in the ability to trans- activate target gene expression. The results demonstrate that the differential transcriptional expression of cytochrome c, through sequential transcription factor phosphorylation, leads to enhanced mitochondrial respiratory capacity upon serum-induced entry to the cell cycle.

Original languageEnglish (US)
Pages (from-to)13134-13141
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number17
DOIs
StatePublished - Apr 28 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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