Impaired coactivator activity of the Gly482 variant of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) on mitochondrial transcription factor A (Tfam) promoter

Biochem Biophys Res Commun. 2006 Jun 9;344(3):708-12. doi: 10.1016/j.bbrc.2006.03.193. Epub 2006 Apr 17.

Abstract

Mitochondrial dysfunction may cause diabetes or insulin resistance. Peroxisome proliferation-activated receptor-gamma (PPAR-gamma) coactivator-1 alpha (PGC-1alpha) increases mitochondrial transcription factor A (Tfam) resulting in mitochondrial DNA content increase. An association between a single nucleotide polymorphism (SNP), G1444A(Gly482Ser), of PGC-1alpha coding region and insulin resistance has been reported in some ethnic groups. In this study, we investigated whether a change of glycine to serine at codon 482 of PGC-1alpha affected the Tfam promoter activity. The cDNA of PGC-1alpha variant bearing either glycine or serine at 482 codon was transfected into Chang human hepatocyte cells. The PGC-1alpha protein bearing glycine had impaired coactivator activity on Tfam promoter-mediated luciferase. We analyzed the PGC-1alpha genotype G1444A and mitochondrial DNA (mtDNA) copy number from 229 Korean leukocyte genomic DNAs. Subjects with Gly/Gly had a 20% lower amount of peripheral blood mtDNA than did subjects with Gly/Ser and Ser/Ser (p<0.05). No correlation was observed between diabetic parameters and PGC-1alpha genotypes in Koreans. These results suggest that PGC-1alpha variants with Gly/Gly at 482nd amino acid may impair the Tfam transcription, a regulatory function of mitochondrial biogenesis, resulting in dysfunctional mtDNA replication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Binding Sites
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Glycine / genetics
  • Glycine / metabolism*
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Hepatocytes / metabolism*
  • Humans
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Mutagenesis, Site-Directed
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Heat-Shock Proteins
  • Mitochondrial Proteins
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • TFAM protein, human
  • Transcription Factors
  • Glycine