JCI - PGC-1 coactivators: inducible regulators of energy metabolism in health and disease

The transcriptional coactivator PGC-1α was identified through its functional interaction with the nuclear receptor PPARγ in brown adipose tissue (BAT), a mitochondria-rich tissue specialized for thermogenesis (1). Thereafter, 2 related coactivators, PGC-1β (also termed PERC) and PGC-1–related coactivator (PRC), were discovered (Figure 1) (2–4). PGC-1α and PGC-1β are preferentially expressed in tissues with high oxidative capacity, such as heart, slow-twitch skeletal muscle, and BAT, where they serve critical roles in the regulation of mitochondrial functional capacity and cellular energy metabolism (1, 3, 5–7). Less is known about the expression patterns and biologic roles of PRC (2, 8).

PGC-1 coactivator docking to specific transcription factors provides a platform for the recruitment of regulatory protein complexes that exert powerful effects on gene transcription (Figure 1). The amino-terminal region of PGC-1 coactivators interacts with proteins containing histone acetyltransferase (HAT) activity, including CREB-binding protein/p300 and steroid receptor coactivator-1 (SRC-1) (9). The HAT activity of this complex remodels histones within chromatin, increasing access of the transcriptional machinery to target genes. A second activating complex, the thyroid hormone receptor–associated protein/vitamin D receptor–interacting protein (TRAP/DRIP, or Mediator) complex, docks on the carboxy terminus of PGC-1α (10). In addition, PGC-1α contains several domains within the carboxy-terminal region that couple pre-mRNA splicing with transcription (11).

Earlier studies involving forced overexpression of PGC-1α or PGC-1β in mammalian cells in culture demonstrated that these coactivators are sufficient to activate gene regulatory programs that drive increased capacity for cellular energy production (3, 5, 7, 12). PGC-1 coactivators effect biologic responses that equip the cell to meet the energy demands of a changing environment, including augmentation of mitochondrial biogenesis, cellular respiration rates, and energy substrate uptake and utilization. The PGC-1 coactivators exert these pleiotropic effects by directly coactivating a specific array of NR and non-NR transcription factors involved in the control of cellular metabolism. Following its discovery as a PPARγ coactivator, Wu et al. demonstrated that PGC-1α coactivates nuclear respiratory factor-1 (NRF-1) and -2 (NRF-2) (5). NRFs regulate expression of mitochondrial transcription factor A (Tfam), a nuclear-encoded transcription factor essential for replication, maintenance, and transcription of mitochondrial DNA (13–15). NRF-1 and NRF-2 also control the expression of nuclear genes encoding respiratory chain subunits and other proteins required for mitochondrial function (16, 17). These discoveries provided mechanistic insight into how PGC-1α activates the broad program of mitochondrial biogenesis and revealed that PGC-1 coactivators were capable of interacting with both NR and non-NR transcription factors.

Although PPARγ, NRF-1, and NRF-2 are key targets of PGC-1α–mediated coactivation, the diverse effects of this coactivator could not be explained by these interactions alone. Multiple PGC-1α partners have now been identified, indicating that this coactivator serves as a pleiotropic regulator of multiple pathways involved in cellular energy metabolism within and outside of the mitochondrion (Figure 2) (18, 19). Since the identification of PPARγ as a PGC-1α transcription factor target, a variety of additional PGC-1 target NRs have been identified. This list includes PPARα (20), PPARβ (21), thyroid hormone receptor (1), retinoid receptors (1), glucocorticoid receptor (22), estrogen receptor (1, 22, 23), farnesyl X receptor (FXR) (24), pregnane X receptor (PXR) (25), hepatic nuclear factor-4 (HNF-4) (26), liver X receptor (LXR) (27), and the estrogen-related receptors (ERRs) (28, 29). In addition, several non-NR PGC-1 partners have been identified, including myocyte enhancer factor-2 (MEF-2) (30), forkhead box O1 (FOXO1) (31), SREBP1 (27), and Sry-related HMG box-9 (Sox9) (32). Through these transcription factor partners, PGC-1 exerts strong effects on many aspects of mitochondrial energy metabolism. For example, PGC-1α coactivates PPARα, a key regulator of genes involved in mitochondrial fatty acid oxidation (20). The PGC-1 target ERRα is an important regulator of mitochondrial energy transduction pathways including fatty acid oxidation and oxidative phosphorylation. In addition, ERRα is capable of cooperating with or directly activating the expression of NRF-1, NRF-2, and PPARα, defining an ERR “cross-regulatory circuit” that theoretically serves as an internal “amplifier” for the PGC-1α cascade (Figure 2). Finally, several of the PGC-1 coactivation targets regulate pathways outside of the mitochondrion — such as HNF-4 and FOXO1 (gluconeogenesis), MEF-2 (glucose transport), SREBP1 (lipogenesis), and Sox9 (chondrogenesis). In addition to serving a booster function, there is evidence that PGC-1 coactivators also confer target gene specificity. For example, selective activation of PPARγ target genes encoding aP2, uncoupling protein-1, and glycerol kinase is dictated, in part, by the PGC-1α/PPARγ interaction on these promoters (1, 33). The mechanisms involved in the selection of specific targets by PGC-1α among tissues in a given physiologic context are an important area of investigation.

The discovery of PGC-1α as a cold-inducible coactivator prompted studies to determine whether its expression is regulated by developmental, physiologic, and dietary cues. One of the first clues that PGC-1α and PGC-1β serve diverse functions in multiple organ systems was the observation that they are expressed in broad, but tissue-enriched, patterns. PGC-1α and PGC-1β are highly expressed in mitochondria-enriched tissues with high energy demands, including BAT, heart, and slow-twitch skeletal muscle (1, 3, 4). PGC-1α is also enriched in brain and kidney. PGC-1α expression is induced in the heart after birth in parallel with a postnatal burst of mitochondrial biogenesis and a shift toward reliance on mitochondrial fatty acid oxidation as the major source of ATP production (12). The PGC1A gene is highly inducible in response to physiologic conditions that demand increased mitochondrial energy production. For example, PGC-1α expression is stimulated by exercise in skeletal muscle (34–38) and by fasting in the heart and liver (12, 26). Interestingly, PGC-1β expression is also induced by fasting, but not cold exposure, indicating that factor-specific upstream regulatory circuits exist (3, 39).

As would be predicted by its inducibility, the expression and activity of PGC-1α are linked to a variety of upstream cellular signaling pathways (Figure 2). In BAT and liver (and likely other tissues), the β-adrenergic/cAMP pathway activates PGC1A gene transcription (1). Calcineurin A and calcium/calmodulin–dependent protein kinase (CaMK) activate PGC-1α expression in striated muscle (40–42). The AMP-activated protein kinase (AMPK) has also been implicated in the control of muscle PGC-1α expression (43). p38 MAPK has been shown to activate PGC-1α by releasing p160-mediated repression and by increasing PGC-1α protein stability (44–46). More recently, NO was shown to activate mitochondrial biogenesis coincident with increased PGC-1α expression in a variety of cell types, including adipocytes and HeLa cells (47). Given the known role of NO as a vasodilator, it is tempting to speculate that this key upstream regulatory pathway coordinately regulates downstream events including an increase in the capacity to utilize oxygen in mitochondria. In addition to phosphorylation, other posttranslational modifications, including acetylation, arginine methylation, and interaction with repressor proteins (e.g., p160), modulate PGC-1α activity (45, 48, 49).

The transcriptional regulatory factors that link upstream signaling pathways to PGC1A gene expression are being delineated. The calcineurin A–mediated activation of the PGC1A promoter is dependent on MEF-2 response elements, whereas CaMK-mediated regulation requires CREB-binding sites (40–42). The transcription factor CREB activates PGC1A gene transcription in hepatocytes, implicating this factor in the PGC-1α–mediated control of gluconeogenesis (50). The forkhead transcription factor FOXO1 activates the human PGC1A promoter in a hepatoma cell line (51), an effect that is suppressed by protein kinase B/Akt signaling, suggesting a mechanism for negative regulation of PGC-1α expression by insulin in the liver.

Given that PGC-1α integrates regulatory input from a variety of upstream regulatory pathways among multiple tissues, in vivo studies have been necessary to define the bona fide biologic functions downstream of this powerful transcriptional coactivator. In vivo studies have been empowered by the development of generalized and conditional transgenic PGC-1α gain-of-function mouse models. In addition, 2 independent generalized PGC-1α–deficient mouse lines (Pgc1a^–/– mice) have been generated using gene targeting strategies (52, 53). Both lines are viable and exhibit multisystem energy metabolic abnormalities that were unveiled by physiologic or nutritional stressors.