p53 and TIGAR regulate cardiac myocyte energy homeostasis under hypoxic stress

Abstract

meostasis is altered in heart failure and may play an important role in pathogenesis. p53 has been implicated in heart failure, and although its role in regulating tumorigenesis is well characterized, its activities on cellular metabolism are just beginning to be understood. We investigated the role of p53 and its transcriptional target gene TP53-induced glycolysis and apoptosis regulator (TIGAR) in myocardial energy metabolism under conditions simulating ischemia that can lead to heart failure. Expression of p53 and TIGAR was markedly upregulated after myocardial infarction, and apoptotic myocytes were decreased by 42% in p53-deficient mouse hearts compared with those in wild-type mice. To examine the effect of p53 on energy metabolism, cardiac myocytes were exposed to hypoxia. Hypoxia induced p53 and TIGAR expression in a p53-dependent manner. Knockdown of p53 or TIGAR increased glycolysis with elevated fructose-2,6-bisphosphate levels and reduced myocyte apoptosis. Hypoxic stress decreased phosphocreatine content and the mitochondrial membrane potential of myocytes without changes in ATP content, the effects of which were prevented by the knockdown of TIGAR. Inhibition of glycolysis by 2-deoxyglucose blocked these bioenergetic effects and TIGAR siRNA-mediated prevention of apoptosis, and, in contrast, overexpression of TIGAR reduced glucose utilization and increased apoptosis. Our data demonstrate that p53 and TIGAR inhibit glycolysis in hypoxic myocytes and that inhibition of glycolysis is closely involved in apoptosis, suggesting that p53 and TIGAR are significant mediators of cellular energy homeostasis and cell death under ischemic stress.TP53-induced glycolysis and apoptosis regulator; hypoxia; metabolism; mitochondria; glycolysis DESPITE SIGNIFICANT THERAPEUTIC ADVANCES, heart failure (HF) remains a leading cause of morbidity and mortality (12, 32). Numerous studies (10, 26) have identified altered cardiac energy homeostasis as a consistent feature of HF. Recently, metabolic-based therapies have attracted much interest as a new approach for the treatment of HF. For example, a metabolic modulator, trimetazidine, shifts the energy source from free fatty acid toward predominantly glucose utilization and improves the cardiac function of patients with idiopathic dilated cardiomyopathy (35). Transgenic mice overexpressing glucose transporter (GLUT)-1 have increased glucose uptake, preserved contractile reserve, and resist the development of HF by chronic pressure overload or ischemic injury (17,20). Based on these promising findings, additional insights into the mechanisms regulating cardiac energy metabolism may be helpful for further advancing our treatment regimens.Cardiac myocytes are known to undergo apoptosis in hypoxia and ischemia-reperfusion (6, 34). Reducing apoptotic cell death and the effect of remodeling after myocardial infarction (MI) have been primary goals, as extensive MI causes severe congestive HF (15). p53 regulates apoptosis, DNA repair, cell cycle progression, and senescence in response...

Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death

“…Because TIGAR cannot localize to the mitochondria in the absence of HIF1α, these results support the suggestion that mitochondrial localization and HK2 binding are important for the survival function of TIGAR in response to hypoxia. Discussion TIGAR has been shown to function as a Fru-2,6-BPase, regulating intracellular Fru-2,6-BP levels and glycolysis under various conditions (16,17,21,23). In this study, we identified an additional function for TIGAR in lowering ROS and maintaining cell survival during hypoxia through a mechanism that is independent of Fru-2,6-BPase activity.…”

“…However, the ability of TIGAR to promote cell survival is cell and context dependent. In cells that highly depend on the maintenance of glycolytic flux for survival, expression of TIGAR correlates with decreased, rather than increased, survival (16,23).…”

Hypoxamirs and Mitochondrial Metabolism

“…p53 is responsible for the up-regulation of GLS2, which indirectly generates a-ketoglutarate for the TCA cycle as previously described (36). In addition, the p53-induced factor, TIGAR, is a key inhibitor of glycolysis (48). Structurally, it resembles fructose-2,6-bisphosphatase phosphofructokinase-2 (FBPase-2), the bisphosphatase domain of the bifunctional glycolytic enzyme, PFK-2/FBPase-2; accordingly, TIGAR has been shown to suppress FBPase-2, leading to a marked decrease in glycolytic flux (5).…”

Novel biomolecule lycopene-reduced graphene oxide-silver nanoparticle enhances apoptotic potential of trichostatin A in human ovarian cancer cells (SKOV3)

“…80 Mitochondrial dysfunction is correlated with two major changes which include changes in the permeabilization of the outer mitochondrial membrane and the loss of the electrochemical gradient. 34,81 Previously, several studies have reported that HDACIs have the potential to trigger depolarization of the mitochondrial membrane, 82,83 which can induce ROS generation. In addition, HDACIs induce the release of proapoptotic Bax and trigger apoptosis via the mitochondrial pathway.…”