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Molecular and Cellular Biology, February 2005, p. 1354-1366, Vol. 25, No. 4
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.4.1354-1366.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Natalie Gleyzer,1 Kristel Vercauteren,1 and Richard C. Scarpulla1*

Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois1

Received 18 June 2004/ Returned for modification 2 August 2004/ Accepted 19 November 2004

In 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-1{alpha} 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-1{alpha} or PRC in cellular systems where mitochondrial biogenesis is induced. Moreover, ectopic expression of PGC-1{alpha} 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.

* Corresponding author. Mailing address: Department of Cell and Molecular Biology, Northwestern University Medical School, 303 East Chicago Ave., Chicago, IL 60611. Phone: (312) 503-2946. Fax: (312) 503-0798. E-mail: rsc248{at}northwestern.edu.

Molecular and Cellular Biology, February 2005, p. 1354-1366, Vol. 25, No. 4
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.4.1354-1366.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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