Control of Mitochondrial Transcription Specificity Factors (TFB1M and TFB2M) by Nuclear Respiratory Factors (NRF-1 and NRF-2) and PGC-1 Family Coactivators

TLDR

Mitochondrial DNA transcription in vertebrates is initiated bidirectionally from HSP and LSP promoters and requires RNA polymerase, Tfam, and the transcription specificity factors TFB1M and TFB2M, which enhance transcription in the presence of Tfam. The study aims to determine whether nuclear respiratory factors NRF‑1 and NRF‑2 regulate the promoters of TFB1M and TFB2M and whether their activity depends on PGC‑1 family coactivators. By identifying NRF recognition sites in both TFB promoters and demonstrating that these sites are necessary for maximal activation by PGC‑1α and PRC, the authors show that NRFs and PGC‑1 coactivators directly control TFB transcription. TFB1M and TFB2M are up‑regulated together with Tfam and either PGC‑1α or PRC during induced mitochondrial biogenesis, and ectopic PGC‑1α expression drives coordinated expression of all three nuclear‑encoded transcription factors and respiratory subunits, underscoring their essential role in biogenesis. Acknowledgments: the work was supported by U.S.

Abstract

AbstractIn vertebrates, mitochondrial DNA (mtDNA) transcription is initiated bidirectionally from closely spaced promoters, HSP and LSP, within the D-loop regulatory region. Early studies demonstrated that mtDNA transcription requires mitochondrial RNA polymerase and Tfam, a DNA binding stimulatory factor that is required for mtDNA maintenance. Recently, mitochondrial transcription specificity factors (TFB1M and TFB2M), which markedly enhance mtDNA transcription in the presence of Tfam and mitochondrial RNA polymerase, have been identified in mammalian cells. Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1α and PRC. The physiological induction of these coactivators has been associated with the integration of NRFs and other transcription factors in a program of mitochondrial biogenesis. Finally, we demonstrate that the TFB genes are up-regulated along with Tfam and either PGC-1α or PRC in cellular systems where mitochondrial biogenesis is induced. Moreover, ectopic expression of PGC-1α is sufficient to induce the coordinate expression of all three nucleus-encoded mitochondrial transcription factors along with nuclear and mitochondrial respiratory subunits. These results support the conclusion that the coordinate regulation of nucleus-encoded mitochondrial transcription factors by NRFs and PGC-1 family coactivators is essential to the control of mitochondrial biogenesis. ACKNOWLEDGMENTSWe thank Daniel P. Kelly of Washington University School of Medicine for the PGC-1α-expressing adenovirus vector and antibodies.This work was supported by United States Public Health Service grant GM32525-22.