The transcriptional co-activator PGC-1 alpha (PGC-1α) was initially identified as a peroxisome proliferator-activated receptor-gamma (PPARγ)-interacting protein from brown adipose tissue (BAT) that was involved in regulating the process of adaptive thermogenesis in response to cold. Subsequent studies determined that the primary function of PGC-1α was to stimulate mitochondrial biogenesis and oxidative metabolism. This is most clearly demonstrated by ectopically expressing PGC-1α in fat or muscle cells which results in a strong induction in the expression of nuclear and mitochondrial-encoded mitochondrial genes as well as stimulation of organelle biogenesis. The expression of PGC-1α is most abundant in tissues that have a demand for energy production. These tissues include BAT, heart, skeletal muscle, kidney, and brain.
The PGC-1α gene (symbol: PPARGC1; also PGC1A) is located on chromosome 4p15.1 spanning 67 kbp and composed of 13 exons that encode a protein comprised of 798 amino acids. Transcription of the PPARGC1 gene results in two mRNA species derived from the use of alternative polyadenylation signals. The PPARGC1 gene does not contain a typical TATA-box in the promoter region. The PGC-1α gene is highly inducible in response to a variety of physiological conditions that require increased mitochondrial energy production. In addition to the effects of cold exposure, PGC-1α expression is stimulated by exercise in skeletal muscle and by fasting in the heart and liver. Interestingly, PGC-1 beta (PGC-1β) expression is also induced by fasting, but not by cold exposure. This difference indicates that factor-specific upstream regulatory circuits exist. The expression of PGC-1α is linked to a variety of upstream cellular signaling pathways. In BAT and liver, the β-adrenergic/cAMP pathway activates PGC-1α gene transcription. Calcineurin A and calcium/calmodulin-dependent protein kinase (CaMK) activate PGC-1α expression in striated muscle. AMP-activated protein kinase (AMPK) has also been shown to exert control of muscle PGC-1α expression. The transcription factor cAMP response-element binding protein (CREB) activates the PPARGC1 gene in the liver indicating that CREB is involved in PGC-1α-mediated control of gluconeogenesis. Nitric oxide (NO) has also recently been shown to activate mitochondrial biogenesis due to increased PGC-1α expression in a variety of tissues.
Subsequent to the identification of PGC-1α, two related co-activators were identified based upon sequence homologies. The co-activators are identified as PGC-1β (also termed PERC for PGC-1-related estrogen receptor coactivator) and PGC-1-related co-activator (PRC). Like the expression of PGC-1α, PGC-1β is preferentially expressed in tissues with high oxidative capacity, such as heart, slow-twitch skeletal muscle, and BAT. In these tissues these two co-activators serve critical roles in the regulation of mitochondrial functional capacity and cellular energy metabolism. Less is currently known about the expression patterns and biological roles of PRC. The PGC-1 family members are conserved in higher vertebrates, including mammals, birds, and fish. A PGC-1 family homologue named Spargel was recently identified in Drosophila that could regulate mitochondrial activity and insulin signaling.
Following the identification of PPARγ as a transcription factor target of PGC-1α several additional PGC-1 family member target nuclear receptors (NRs) have been identified. This list includes PPARα, PPARβ/δ, thyroid hormone receptor (TR), retinoid receptors (RARs and RXRs), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), estrogen receptor (ER), estrogen-related receptors (ERRs), vitamin D receptor (VDR), thyroid hormone receptor (TR), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), liver X receptors (LXRs), pregnane X receptor (PXR), and hepatic nuclear factor-4 alpha (HNF-4α). In addition to the broad list of NR targets of PGC-1 family members, several non-NR PGC-1 partners have been identified. These include forkhead box O1 (FOXO1), SREBP1, myocyte enhancer factor-2 (MEF-2), and Sry-related HMG box-9 (Sox9). As a consequence of these transcription factor partners, the PGC-1 family co-activators effect strong regulation upon many aspects of not only mitochondrial energy metabolism but also many other important metabolic pathways. For example, HNF-4α and FOXO1 are involved in the regulation of genes of gluconeogenesis, MEF-2 is important in glucose transport, SREBP1 regulates numerous genes involved in lipid and cholesterol metabolism, and Sox9 is involved in the control of chondrogenesis. Another critically important example of the broad regulation of PGC-1 family members is the PGC-1α-medicated co-activation of PPARα. PPARα is a primary regulator of the transcription of genes involved in mitochondrial fatty acid oxidation.
In addition to the NRs indicated above it has been shown that PGC-1α co-activates nuclear respiratory factor-1 (NRF-1) and -2 (NRF-2). NRFs regulate expression of mitochondrial transcription factor A (Tfam also mtTFA), a nuclear-encoded transcription factor essential for replication, maintenance, and transcription of mitochondrial DNA. NRF-1 and NRF-2 also control the expression of nuclear genes encoding protein subunits of the oxidative-phosphorylation machinery as well as additional proteins required for overall mitochondrial function. Although PPARγ, NRF-1, and NRF-2 are key targets of PGC-1α-mediated co-activation, the diverse effects exerted by PGC-1α could not be explained by its interactions with just these three transcription factors. As indicated above, multiple PGC-1α interaction partners have now been identified. The plethora of transcription factor interactions indicates that PGC-1α serves as a pleiotropic regulator of multiple pathways involved in cellular energy metabolism within as well as outside of the mitochondrion.
The interaction of PGC-1α with specific transcription factors generates a docking platform that serves to recruit additional transcriptional regulatory protein complexes. The formation of these protein complexes is what is required to effect changes in the rates of transcription of target genes. The N-terminus of PGC-1 co-activators has a strong transcriptional activation domain that interacts with proteins containing histone acetyltransferase (HAT) activity. Two of these HAT complex proteins that bind PGC-1α are cAMP response element-binding protein (CREB)-binding protein (CBP)/p300 (CBP/p300) and steroid receptor coactivator-1 (SRC-1). The HAT activity of these complexes acetylates histones leading to a remodeling of chromatin structure into a state that is permissive for transcriptional activation. A second activating complex, the thyroid hormone receptor-associated protein/vitamin D receptor-interacting protein (TRAP/DRIP, also referred to as Mediator) complex, docks on the C-terminus of PGC-1α. This C-terminal region also interacts with the switch/sucrose non-fermentable (SWI/SNF) chromatin-remodeling complex through its interaction with brahma-related gene 1 (BRG1)-associated factor 60a (BAF60a; also known as SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 1: SMARCD1). In addition to the ability of PGC-1α to serve as a docking site for these chromatin remodeling complex proteins, it also contains several C-terminal domains that couple pre-mRNA splicing to the process of transcription.
The PGC-1α transcriptional co-activator complex is also able to displace transcriptional repressor proteins, such as histone deacetylase (HDAC) and small heterodimer partner (SHP), from the promoter regions of its target genes. The ability of PGC-1 family members to recruit transcriptional activator proteins and to displace transcriptional repressor proteins provides additional and alternative mechanisms for regulation of gene expression. PGC-1α and PGC-1β share extensive protein domain similarities and several regions of conserved amino acids. These include the LXXLL motif that interacts with nuclear receptors and the host cell factor 1 interacting motif. PRC also contains a transcriptional activation domain and and RNA-binding domain, but overall has more limited homology to PGC-1α and PGC-1β. Both PGC-1α and PGC-1β robustly regulate mitochondrial oxidative metabolism.
The activating effects of PGC-1α on mitochondrial gene expression are exerted through its co-activation of NRF1 and NRF2 as well as the estrogen-related receptor α (ERRα). The induction of NRF1 and NRF2 by PGC-1α not only results in increased expression of Tfam (mtTFA), as indicated above, but of other mitochondrial subunits of the electron transport chain complex such as β-adenosinetriphosphate (ATP) synthase, cytochrome c, and cytochrome oxidase IV. Following expression of the Tfam gene, the protein translocates to mitochondrial matrix where it stimulates mitochondrial DNA replication and mitochondrial gene expression. ERRα is an important regulator of mitochondrial energy producing pathways that includes 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 the result of which is an ERR cross-regulatory circuit that theoretically serves as an internal amplifier for the PGC-1α cascade.
PGC-1α is subject to extensive post-translational modifications. These modifications, that occur in response to nutritional and hormonal signals, include acetylation, phosphorylation, methylation, and SUMOylation. These modifications allow fine-tuning of PGC-1α activities in a context-dependent manner. Acetylation of PGC-1α occurs at several lysine residues and is catalyzed by the acetyl transferase identified as general control of amino acid synthesis 5 (GCN5). The acetylation of PGC-1α alters its localization within the nucleus and inhibits its transcriptional activity. Conversely, deacetylation of PGC-1α is accomplished via the action of sirtuin 1 (SIRT1) and this increases PGC-1α activity on gluconeogenic gene transcription in the liver. PGC-1β is also acetylated at multiple sites, however, the biological significance is not yet as clearly defined as it is for PGC-1α. PGC-1α is phosphorylated by both p38 MAPK and AMPK in skeletal muscle, leading to a more stable and active protein. In experiments using C2C12 cells (a mouse myoblast cell line) it has been shown that AMPK-mediated phosphorylation primes PGC-1α for deacetylation by SIRT1. However, not all PGC-1α phosphorylations are activating. Phosphorylation of PGC-1α by AKT/protein kinase B (PKB), downstream of the insulin signaling cascade in the liver, decreases its stability and transcriptional activity. PGC-1α is also methylated at several arginine residues in the C-terminal region by protein arginine methyltransferase. PGC-1α can also undergo SUMOylation in conserved lysine residue 183 which results in attenuation of its transcriptional activity.
Brown fat: In contrast to white adipose tissue (WAT), whose primary physiological function is energy storage, the main function of BAT is energy dissipation, largely in the form of heat. As such, BAT is the major organ responsible for adaptive thermogenesis during cold exposure in rodents. The expression of PGC-1α is strongly induced in BAT by cold temperature which occurs downstream of the β-adrenergic receptor/cAMP pathway and sympathetic nervous system activity. The activation of PGC-1α turns on several key components of the adaptive thermogenic program, including the stimulation of fuel uptake, mitochondrial fatty-acid β-oxidation, and stimulation of the expression of uncoupling protein 1 (UCP1, also called thermogenin). PGC-1α interacts with other nuclear hormone receptors such as PPARα, retinoic acid receptor, and thyroid receptor to enhance UCP1 expression. UCP1 dissipates the mitochondrial proton gradient generated during the process of oxidative-phosphorylation thereby, uncoupling oxidative phosphorylation from ATP production with the release of the energy as heat. PGC-1α-deficient mice are unable to defend against cold stress due to thermogenic defects. Expression of PGC-1β is induced during the process of adipocyte differentiation in both WAT and BAT. Interestingly, while the expression of PGC-1β is not cold inducible, a deficiency in this co-activator also impairs adaptive thermogenesis, suggesting that both PGC-1α and PGC-1β play non-redundant functions in the oxidation of fuels such as lipids and thermogenic responses.
Brain: Recent studies of mice with neuron-specific PGC-1α inactivation indicate that this co-factor plays a crucial role in neuronal function and energy balance. PGC-1α knock-out (KO) mice display spongioform lesions in several brain areas, predominantly in the striatum, and exhibit behavioral abnormalities such as marked hyperactivity and frequent limb clasping. Of clinical significance to humans is the fact that striatal degeneration with hyperactivity is reminiscent of Huntington disease (HD), potentially implicating PGC-1α in the selective vulnerability of striatal neurons in HD. The mutant huntingtin protein that accumulates in HD brain interferes with PGC-1α function by repressing its transcription. Impaired PGC-1α expression and mitochondrial function contributes to neurodegeneration in susceptible neurons. In addition, PGC-1α plays an important role in the regulation of genes responsible for the detoxification of reactive oxygen species (ROS), including copper/zinc superoxide dismutase (SOD1), manganese SOD (SOD2), and glutathione peroxidase 1 (GPx1). The involvement of PGC-1α in neuronal ROS detoxification protects dopaminergic neurons from degeneration caused by oxidative stress. Given that PGC-1α expression is impaired in the striatum of HD patients raises the possibility that there is therapeutic potential in the development of PGC-1α activating compounds within the brain.
Heart: The heart has a very large energy demand that is satisfied by a high capacity mitochondrial oxidation system. Given the mitochondrial needs of cardiac muscle, it is not surprising that PGC-1α and PGC-1β are highly expressed in this organ. Several lines of evidence indicate that PGC-1α is important in the control of metabolic pathways of energy production in the heart during development as well as in response to physiological stressors. The exact functions of PGC-1β and/or PRC in the heart have not yet been fully defined, Expression of cardiac PGC-1α is induced shortly after birth as the heart shifts to mitochondrial fatty acid oxidation as its primary source of energy. Fasting, which is a physiological stimulus that dramatically increases the reliance of the heart on mitochondrial fat oxidation for ATP production, also strongly induces PGC-1α expression in the heart. PGC-1α co-activates PPARα and ERRα both of which are transcription factors that control expression of genes involved in fatty acid oxidation and mitochondrial respiratory function in the heart. In cardiac myocytes, forced overexpression of PGC-1α results in coupled mitochondrial respiration which is in contrast to the effects of PGC-1α in BAT which causes uncoupled respiration. Overexpression of PGC-1α in neonatal mouse heart results in a dramatic expansion of mitochondria within the cardiac myocytes. In contrast, in adult mouse hearts, forced overexpression of PGC-1α results in a modest mitochondrial biogenic response followed by cardiomyopathy associated with mitochondrial ultrastructural abnormalities. Additional studies link abnormal expression of PGC-1α to the pathogenesis of heart failure. What is not yet clear is whether PGC-1α plays an etiological role in the pathogenesis of heart failure.
Skeletal muscle: The expression of PGC-1α is enriched in skeletal muscle, particularly in oxidative fiber types which are the slow-twitch fibers. Experimental animal studies have shown that both short-term exercise and endurance training activate PGC-1α expression in skeletal muscle. Similar studies in humans have have also demonstrated the dramatic induction of PGC-1α in response to acute bouts of exercise or endurance training. These studies in humans have indicated that PGC-1α levels are increased mainly in type IIa fibers (intermediate fast-twitch fibers) after endurance training. The calcineurin A and CaMK signaling pathways are linked to expression of the PGC-1α gene in through MEF-2 factors. The p38 MAPK and AMPK pathways have also been implicated in the control of PGC-1α expression in skeletal muscle after exercise training. In mice, the forced expression of PGC-1α results in an increased proportion of oxidative or type I muscle fibers that coincides with an increase in the expression of markers of mitochondrial biogenesis. Results such as this indicate that PGC-1α is sufficient to drive the slow twitch skeletal muscle program. Conversely, in PGC-1α knock-out mice there is diminished mitochondrial number and respiratory capacity in slow-twitch fibers, whereas, in fast-twitch fibers mitochondrial function and density are normal. These results strongly implicate PGC-1α signaling as a key mediator of energy metabolism as well as the structural adaptation of muscle to exercise. PGC-1α has also been shown to be important in the regulation of muscle glucose metabolism evidenced by the strong activation of GLUT4 expression in skeletal muscle cells in culture by co-activating MEF-2c. PGC-1α has also been shown to repress glucose oxidation in muscle cell lines by activating the expression of the gene encoding pyruvate dehydrogenase kinase 4 (PDHK4). Activation of PDHK4 by PGC-1α involves interaction with ERRα. The inhibition of glucose oxidation coupled to increased muscle glucose uptake (via GLUT4) could serve to replenish muscle glycogen stores to prepare for the next bout of exercise. These results strongly suggest that PGC-1α controls muscle fuel selection by increasing fatty acid oxidation while simultaneously restricting glucose oxidation.
Liver: The level of PGC-1α and PGC-1β expression in the liver is low compared to that of other tissues that rely on aerobic metabolism for ATP production. However, fasting induces a dramatic increase in hepatic expression of both genes. During short-term starvation, oxidation of fatty acids becomes a key source of carbon atom for ATP production, and the generation of ketone bodies. PGC-1α and PGC-1β both activate expression of PPARα target genes involved in hepatic fatty acid oxidation. In addition, during periods of fasting, hepatic catabolism of triglycerides provides the 3-carbon substrate, glycerol, for gluconeogenesis. During periods of fasting, when blood glucose levels fall, the α-cells of the pancreas release glucagon. Glucagon binding to its receptor, on hepatocytes, results in the activation of PKA which, among many targets, phosphorylates and activates the transcription factor CREB (cAMP-response element binding protein). Active CREB then transcriptionally activates numerous genes including PGC-1α. This fasting-induced expression of PGC-1α is required for the full initiation of hepatic gluconeogenesis since PGC-1α co-activates the transcription factors HNF-4α and FOXO1 to drive expression of genes involved in this metabolic pathway. With respect to transcriptional activation of gluconeogenesis, CREB activates the PEPCK gene, while PGC-1α alone, and in combination with HNF-4α and FOXO1, activates the PEPCK gene, the fructose-1,6-bisphosphatase gene, and the glucose-6-phosphatase gene. Conversely, PGC-1β does not activate this pathway.
The deacetylase SIRT1 also exerts critical posttranslational regulatory control of gluconeogenic gene expression via deacetylation and activation of PGC-1α. Differences in the roles of PGC-1α and PGC-1β in the regulation of hepatic metabolism have been uncovered in experimental animals. Administration of a diet enriched in saturated or trans-fatty acids leads to an acute induction of hepatic PGC-1β expression without altering PGC-1α expression. Overexpression of PGC-1β in the liver stimulates hepatic triglyceride production and secretion, resulting in circulating hypertriglyceridemia and hypercholesterolemia. Conversely, activation of PGC-1α in liver leads to a diminished level of triglyceride production and secretion. These differences in expression are due to the fact that PGC-1β, but not PGC-1α, activates the expression of genes involved in lipogenesis and triglyceride secretion via direct co-activation of SREBP1c. Given the importance of hepatic lipid metabolic derangements in common diseases such as nonalcoholic steatotic hepatitis (NASH) and alcoholic liver disease, as well as the link between liver insulin resistance and diabetes, the PGC-1 regulatory circuits functioning within the liver represent potential new therapeutic targets for intervention in hepatic disease.
PGC-1α in insulin resistance and diabetes mellitus: Recent studies in animal models and in humans link altered PGC-1α signaling to glucose intolerance, insulin resistance, and diabetes. However, the role of PGC-1α as a protective factor versus mediator of disease progression is unclear, particularly given that its predicted effects on insulin sensitivity and glucose tolerance vary across tissues. A potential association between PGC-1α and diabetes was suggested by genome-wide susceptibility studies showing a common polymorphism in the coding region of the PGC1A gene (a serine for glycine substitution at codon 482: G482S), as well as a promoter region mutation, are associated with an increased risk of type 2 diabetes. However, additional studies have not demonstrated a clear link between these mutations in the PGC1A gene and type 2 diabetes. Despite these differences it is known that PGC-1α activity is strongly activated in diabetic liver similarly to the induction in the fasted state. This diabetic induction of PGC-1α could potentially contribute to increased hepatic glucose production that, in turn, would contribute to the hyperglycemia of type 2 diabetes. In addition, PGC-1α may promote insulin resistance directly by inducing the expression of TRB3 (tribbles homolog 3; tribbles is a Drosophila protein that inhibits mitosis) which is an inhibitor of AKT/PKB signaling, a critical downstream component of the insulin signaling pathway. PGC-1α is also activated in the pancreatic β-cell in several rodent models of obesity and type 2 diabetes. However, in contrast to results in liver and the β-cell, evidence from experiments in skeletal muscle indicate that PGC-1α may be protective from the development of insulin resistance. As pointed out in the section above, PGC-1α activates expression of GLUT4 in skeletal muscle resulting in increased glucose uptake by this tissue which in turn significantly contributes to reducing plasma glucose levels. Also, experimental overexpression of PGC-1β within skeletal muscle protects mice from high-fat diet-induced obesity and insulin resistance. Given that inherited deficiencies in mitochondrial function are linked to the development of systemic metabolic defects and diabetes, the role of PGC-1α as a critical booster of mitochondrial function indicates that this gene is a viable target for preventing insulin resistance secondary to mitochondrial dysfunction. Of significance to this latter point, several studies in humans have shown an inverse correlation between muscle PGC-1α levels and consequent effects on mitochondrial function with insulin resistance and diabetes. However, there is some controversy in these observations since a separate recent study did not find a correlation between muscle mitochondrial derangements and PGC-1α levels in insulin-resistant humans. The use of PGC1A knock-out mice should provide insight into the paradoxical tissue-specific actions of PGC-1α on systemic glucose metabolism and insulin sensitivity. These knock-out mice are modestly protected against insulin resistance caused by a high-fat diet despite reduced mitochondrial respiratory capacity in skeletal muscle. It is suggested that this insulin-sensitizing effect is related to the reduced hepatic glucose production via the gluconeogenic pathway that contributes to the enhanced glucose tolerance in the knock-out mice. As pointed out above, liver-specific overexpression of PGC-1α results in increased hepatic glucose production contributing to the development of obesity-related diabetes.
PGC-1α and metabolic diseases: Given that PGC-1α regulates multiple aspects of energy metabolism, it is not surprising that abnormal PGC-1α activity has been associated with several pathological conditions. The expression of PGC-1α and its target genes involved in mitochondrial oxidative phosphorylation is significantly decreased in the skeletal muscle of patients with type 2 diabetes. Similar reduction of PGC-1α expression was also observed in the adipose tissue of insulin-resistant and morbidly obese individuals. Interestingly, thiazolidinediones, an important class of antidiabetic drugs, can enhance the expression of PGC-1α and mitochondrial biogenesis in white adipose tissue. While these observations support a potentially beneficial role of PGC-1α in insulin resistance and type 2 diabetes, several studies suggested distinct actions of PGC-1α in other tissues. For example, PGC-1α expression is elevated in the liver of both type 1 and type 2 diabetic mouse models. Furthermore, PGC-1α has been shown to stimulate hepatic glucose production and suppress β-cell energy metabolism and insulin release in mice. Paradoxically, transgenic expression of PGC-1α in skeletal muscle leads to robust mitochondrial biogenesis but also causes insulin resistance, likely the result of imbalance of lipid uptake and oxidation. In addition, a common polymorphism of the PGC-1α gene (G482S), which apparently reduces PGC-1α activity, has been linked to increased risk of type 2 diabetes. In the cardiovascular system, PGC-1α expression is also decreased in hypertrophic heart. PGC-1α null mice display accelerated cardiac dysfunction and clinical signs of heart failure. In contrast, PPARα ligand-dependent transcriptional activity and co-activation by PGC-1α are enhanced in the heart by stress including ischemia and hypoxia. The role of PGC-1α, in response to hypoxia, relates to the fact that it leads to increased expression of numerous genes that are known to be regulated by hypoxia inducible factor 1 (HIF-1). PGC-1α-dependent induction of HIF-1 target genes results from induced stabilization of the HIF-1α protein of the HIF-1 complex not via transcriptional coactivation of the genes encoding HIF-1 protein subunits.
In peripheral vessel tissues, downregulation of PGC-1α expression was observed in vascular smooth muscle cells (VSMCs) treated by oleic acid and high glucose. Restoration of PGC-1α has beneficial effects on VSMCs and endothelial cells. In this context, PGC-1α appears to play an important role in ROS metabolism and defense against oxidative stress. These observations indicate that PGC-1α is an important factor in the regulation of cardiovascular function. Abnormalities in mitochondrial function are associated with neurodegenerative disorders including Parkinson disease, Alzheimer disease, and HD. Levels of PGC-1α are reduced in the brain of HD patients due to repression of PGC-1α gene expression by mutant huntingtin, leading to mitochondrial defects and increased oxidative stress. Expression of PGC-1α partially reverses the toxic effects and provides neuroprotection in the HD mutant mouse. In the peripheral nervous system, PGC-1α has been shown to regulate gene expression at the neuromuscular junction and influences expression of acetylcholine receptors in muscle fibers. In addition, elevated PGC-1α levels protect neural cells in culture from cell death caused by oxidative-stressor through its induction of antioxidant genes. Energy metabolism in cancer cells differs fundamentally from that in its normal counterparts. In general, cancer cells have high glycolytic activity and prefer glucose as a fuel source, a phenomenon known as the Warburg effect. The switch from oxidative-phosphorylation to glycolysis occurs even in the presence of sufficient oxygen. This aerobic glycolysis has been postulated to enhance cancer cell proliferation and survival. Interestingly, reduced expression of PGC-1α has been observed in human breast cancer, colon cancer, liver cancer, and ovarian cancer. These findings suggest that PGC-1α is a potentially important regulator of cancer cell metabolism and contributes to altered metabolic function in cancer cells.