Expression of adenine nucleotide translocase (ANT) isoform genes is controlled by PGC-1α through different transcription factors.

Abstract

Adenine nucleotide translocase (ANT) isoforms are mitochondrial proteins encoded by nuclear DNA that catalyze the exchange of ATP generated in the mitochondria for ADP produced in the cytosol. The aim of this study was to determine the role of the transcriptional coactivator PGC-1α (peroxisome proliferator-activated receptor-γ [PPAR-γ] coactivator 1α), a master regulator of mitochondrial oxidative metabolism, in the regulation of the expression of ANT isoform genes and to identify the transcription factors involved. We found that PGC-1α overexpression induced the expression of all ANT human and mouse isoforms but to different degrees. The transcription factor ERRα was involved in PGC-1α-induced expression of all human ANT isoforms (hANT1-3) in HeLa cells as well as in the regulation of mouse isoforms (mANT1-2) in C2C12 myotubes and 3T3-L1 adipocytes, even though ANT isoforms have important physiological differences and are regulated in a tissue-specific manner. In addition to ERRα, PPARδ and mTOR pathways were involved in the induction of mANT1-2 by PGC-1α in C2C12 myotubes, while PPARγ was involved in PGC-1α-regulation of mANT1-2 in 3T3-L1 adipocytes. Furthermore, the regulation of mANT genes by PGC-1α was also observed in vivo in knockout mouse models lacking PGC-1α. In summary, our results show that the regulation of genes encoding ANT isoforms is controlled by PGC-1α through different transcription factors depending on cell type.