Nuclear respiratory factor 2 senses changing cellular energy demands and its silencing down-regulates cytochrome oxidase and other target gene mRNAs

Gene. 2006 Jun 7;374:39-49. doi: 10.1016/j.gene.2006.01.009. Epub 2006 Mar 3.

Abstract

Cytochrome c oxidase (COX), the terminal enzyme of the electron transport chain, is a bigenomic enzyme with 13 subunits. The mechanism coordinating the transcription of these subunits is poorly understood. We investigated the role of nuclear respiratory factor-2 (NRF-2) in intragenomic regulation of nuclear COX genes. Vector-mediated short-hairpin RNA interference against NRF-2alpha reduced all 10 COX nuclear subunit mRNAs and mRNAs of other genes involved in mitochondrial function/biogenesis. NRF-2 binding site was necessary for the rat COX 4i1 promoter to down-regulate in response to decreased energy demands in primary neurons. Over-expression of NRF-2 protein prevented the down-regulation of transcriptional activity by TTX. Finally, NRF-2 binding sites in isolation were sufficient for modulating COX subunit 4i1 and 6A1 promoters' activity in response to decreased energy demand. These results indicate that NRF-2 is a vital part of a molecular mechanism that senses upstream energy signals and modulates COX transcriptional levels in mammalian cells.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Binding Sites
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Down-Regulation
  • Electron Transport Complex IV / genetics*
  • Energy Metabolism*
  • Gene Expression Regulation, Enzymologic*
  • Gene Silencing
  • Genetic Vectors
  • Mice
  • NIH 3T3 Cells
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Nuclear Respiratory Factors / genetics
  • Nuclear Respiratory Factors / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA Interference
  • RNA, Messenger / metabolism*
  • RNA, Small Interfering / metabolism
  • Rats
  • Tetrodotoxin / toxicity
  • Transcription, Genetic

Substances

  • Nuclear Respiratory Factors
  • RNA, Messenger
  • RNA, Small Interfering
  • Tetrodotoxin
  • Electron Transport Complex IV