Transcriptional integration of mitochondrial biogenesis

Abstract

Gene regulatory factors encoded by the nuclear genome are essential for mitochondrial biogenesis and function. Some of these factors act exclusively within the mitochondria to regulate the control of mitochondrial transcription, translation and other functions. Others govern the expression of nuclear genes required for mitochondrial metabolism and organelle biogenesis. The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators plays a major role in transducing and integrating physiological signals governing metabolism, differentiation and cell growth to the transcriptional machinery controlling mitochondrial functional capacity. Thus, the PGC-1 coactivators serve as a central component of the transcriptional regulatory circuitry that coordinately controls the energy-generating functions of mitochondria in accordance with the metabolic demands imposed by changing physiological conditions, senescence, and disease.

Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle

“…multiple nuclear transcriptional regulators, including PGC-1a, PGC-1b, NRF1, GABP, PPARa, PPARd, and ERRs (13)(14)(15)(53)(54)(55). Perm1 also led to enhanced levels of PGC1a and ERRa, suggesting that the effects of Perm1 on gene expression are at least in part mediated through increases in these transcriptional regulators.…”

A Role for Peroxisome Proliferator-activated Receptor γ Coactivator 1 (PGC-1) in the Regulation of Cardiac Mitochondrial Phospholipid Biosynthesis

“…The PGC-1 coactivators are key regulators of mitochondrial function and biogenesis (6,7). Studies over the past decade have shown that this family of inducible transcriptional coregulators serve to coordinately regulate the expression of nuclear and mitochondrial genes encoding enzymes and proteins involved in virtually all aspects of mitochondrial energy transduction and ATP synthesis in mitochondrion-rich tissues such as heart, brown adipose tissue, and skeletal muscle (38,39).…”

“…Extensive studies in cells and in mice have revealed the importance of the PGC-1 coactivators as "boosters" of transcription factors involved in the regulation of nuclear and mitochondrial genes encoding enzymes and proteins involved in mitochondrial energy transduction and ATP synthesis (6,7). Loss-and gainof-function studies in mice have demonstrated the importance of PGC-1␣ and -␤ in mitochondrial biogenesis in the developing heart and other mitochondrion-rich tissues (8 -13).…”

Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

“…However, an important regulatory control is the coordinated transcription of genes encoding for these proteins that will determine the rate of synthesis and cellular concentrations that will promote and contribute to mitochondrial mass. In mammalian cells, this transcriptional control involves the PGC-1 pathway and its interactions with transcription factors including NRFs and YY1 that are bound to promoters of mitochondrial import genes (Blattler et al 2012b;Scarpulla et al 2012). Whether there is selectivity or specificity among the different import pathways described here is currently unknown.…”

“…Another level of control of this mitochondrial transcriptional machinery is by inducing amounts of its components. Along these lines elements essential to mitochondrial transcription, such as TFAM, TFB2M, MTERF, and POLRMT, are regulated through the transcriptional coactivators PGC-1a and PGC-1b through their interaction with NRFs, ERRs, and YY1 (Mootha et al 2004;Blattler et al 2012b;Scarpulla et al 2012).…”