Impaired coactivator activity of the Gly 482 variant of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) on mitochondrial transcription factor A (Tfam) promoter

Abstract

Mitochondrial dysfunction may cause diabetes or insulin resistance. Peroxisome proliferation-activated receptor-γ (PPAR-γ) coactivator-1 α (PGC-1α) increases mitochondrial transcription factor A (Tfam) resulting in mitochondrial DNA content increase. An association between a single nucleotide polymorphism (SNP), G1444A(Gly482Ser), of PGC-1α 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-1α affected the Tfam promoter activity. The cDNA of PGC-1α variant bearing either glycine or serine at 482 codon was transfected into Chang human hepatocyte cells. The PGC-1α protein bearing glycine had impaired coactivator activity on Tfam promoter-mediated luciferase. We analyzed the PGC-1α 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-1α genotypes in Koreans. These results suggest that PGC-1α variants with Gly/Gly at 482nd amino acid may impair the Tfam transcription, a regulatory function of mitochondrial biogenesis, resulting in dysfunctional mtDNA replication.