Transcriptional activators and coactivators in the nuclear control of mitochondrial function in mammalian cells

Abstract

The biogenesis and function of mitochondria rely upon the regulated expression of nuclear genes. Recent evidence points to both transcriptional activators and coactivators as important mediators of mitochondrial maintenance and proliferation. Several sequence-specific activators including NRF-1, NRF-2, Sp1, YY1, CREB and MEF-2/E-box factors, among others, have been implicated in respiratory chain expression. Notably, recognition sites for NRF-1, NRF-2 and Sp1 are common to most nuclear genes encoding respiratory subunits, mitochondrial transcription and replication factors, as well as certain heme biosynthetic enzymes and components of the protein import machinery. Moreover, genetic evidence supports a role for NRF-1 in the maintenance of mtDNA during embryonic development. Despite these advances, the means by which multiple transcription factors are integrated into a program of mitochondrial biogenesis remains an open question. New insight into this problem came with the discovery of the transcriptional coactivator, PGC-1. This cofactor is cold inducible in brown fat and interacts with multiple transcription factors to orchestrate a program of adaptive thermogenesis. As part of this program, PGC-1 can up-regulate nuclear genes that are required for mitochondrial biogenesis in part through a direct interaction with NRF-1. Ectopic expression of PGC-1 induces the expression of respiratory subunit mRNAs and leads to mitochondrial proliferation in both cultured cells and transgenic mice. More recently, PRC was characterized as a novel coactivator that shares certain structural similarities with PGC-1 including an activation domain, an RS domain and an RNA recognition motif. However, unlike PGC-1, PRC is not induced significantly during thermogenesis but rather is cell-cycle regulated in cultured cells under conditions where PGC-1 is not expressed. PRC has a transcriptional specificity that is very similar to PGC-1, especially in its interaction with NRF-1 and in the activation of NRF-1 target genes. These regulated coactivators may provide a means for integrating sequence-specific activators in the biogenesis and function of mitochondria under diverse physiological conditions.