MITOCHIP assessment of differential gene expression in the skeletal muscle of Ant1 knockout mice: coordinate regulation of OXPHOS, antioxidant, and apoptotic genes

Biochim Biophys Acta. Jul-Aug 2008;1777(7-8):666-75. doi: 10.1016/j.bbabio.2008.03.015. Epub 2008 Mar 28.

Abstract

Genetic inactivation of the nuclear-encoded mitochondrial heart-muscle adenine nucleotide translocator-1 (ANT1), which exports mitochondrial ATP to the cytosol in both humans (ANT1-/-) and mice (Ant1-/-), results in lactic acidosis and mitochondrial cardiomyopathy and myopathy, the latter involving hyper-proliferation of mitochondria, induction of oxidative phosphorylation (OXPHOS) enzymes, increased reactive oxygen species (ROS), and excessive mtDNA damage. To understand these manifestations, we analyzed Ant1-/- mouse skeletal muscle for changes in gene expression using our custom 644 and 1087 gene MITOCHIP microarrays and for changes in the protein levels of key mitochondrial transcription factors. Thirty-four mRNAs were found to be up-regulated and 29 mRNAs were down-regulated. Up-regulated mRNAs included the mitochondrial DNA (mtDNA) polypeptide and rRNA genes, selected nuclear-encoded OXPHOS genes, and stress-response genes including Mcl-1. Down-regulated mRNAs included glycolytic genes, pro-apoptotic genes, and c-Myc. The mitochondrial regulatory proteins Pgc-1alpha, Nrf-1, Tfam, and myogenin were up-regulated and could account for the induction of the OXPHOS and antioxidant enzymes. By contrast, c-Myc levels were reduced and might account for a reduction in apoptotic potential. Therefore, the Ant1-/- mouse skeletal muscle demonstrates that energy metabolism, antioxidant defenses, and apoptosis form an integrated metabolic network.

Publication types

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

MeSH terms

  • Adenine Nucleotide Translocator 1 / deficiency*
  • Adenine Nucleotide Translocator 1 / genetics*
  • Animals
  • Antioxidants / metabolism*
  • Apoptosis / genetics*
  • Cloning, Molecular
  • Energy Metabolism
  • Mice
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis*
  • Oxidative Phosphorylation*
  • Polymerase Chain Reaction
  • RNA / genetics
  • Recombinant Proteins / metabolism
  • Up-Regulation

Substances

  • Adenine Nucleotide Translocator 1
  • Antioxidants
  • Recombinant Proteins
  • RNA