title: Impaired coactivator activity of the Gly482 variant of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) on mitochondrial transcription factor A (Tfam) promoter.
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.
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Yon-Sik
authors.initials: YS
authors.lastname: Choi
authors.forename: Jung-Man
authors.initials: JM
authors.lastname: Hong
authors.forename: Sunny
authors.initials: S
authors.lastname: Lim
authors.forename: Kyung Soo
authors.initials: KS
authors.lastname: Ko
authors.forename: Youngmi Kim
authors.initials: YK
authors.lastname: Pak
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005998:Glycine / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C499631:TFAM protein, human; D014157:Transcription Factors; D005998:Glycine