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Cellular and Molecular Life Sciences :... May 2015Enhanced glycolysis in cancer, called the Warburg effect, is a well-known feature of cancer metabolism. Recent advances revealed that the Warburg effect is coupled to... (Review)
Review
Enhanced glycolysis in cancer, called the Warburg effect, is a well-known feature of cancer metabolism. Recent advances revealed that the Warburg effect is coupled to many other cancer properties, including adaptation to hypoxia and low nutrients, immortalisation, resistance to oxidative stress and apoptotic stimuli, and elevated biomass synthesis. These linkages are mediated by various oncogenic molecules and signals, such as c-Myc, p53, and the insulin/Ras pathway. Furthermore, several regulators of glycolysis have been recently identified as oncogene candidates, including the hypoxia-inducible factor pathway, sirtuins, adenosine monophosphate-activated kinase, glycolytic pyruvate kinase M2, phosphoglycerate mutase, and oncometabolites. The interplay between glycolysis and oncogenic events will be the focus of this review.
Topics: Carcinogenesis; Cell Hypoxia; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; Metabolic Networks and Pathways; Models, Biological; Neoplasms; Ubiquitination
PubMed: 25609364
DOI: 10.1007/s00018-015-1840-3 -
Frontiers in Cell and Developmental... 2022Phosphoglycerate mutase 2 (PGAM2) is a critical glycolytic enzyme that is highly expressed in skeletal muscle. In humans, naturally occurring mutations in...
Phosphoglycerate mutase 2 (PGAM2) is a critical glycolytic enzyme that is highly expressed in skeletal muscle. In humans, naturally occurring mutations in Phosphoglycerate mutase 2 have been etiologically linked to glycogen storage disease X (GSDX). Phosphoglycerate mutase 2 activity is regulated by several posttranslational modifications such as ubiquitination and acetylation. Here, we report that Phosphoglycerate mutase 2 activity is regulated by sumoylation-a covalent conjugation involved in a wide spectrum of cellular events. We found that Phosphoglycerate mutase 2 contains two primary SUMO acceptor sites, lysine (K)49 and K176, and that the mutation of either K to arginine (R) abolished Phosphoglycerate mutase 2 sumoylation. Given that K176 is more highly evolutionarily conserved across paralogs and orthologs than K49 is, we used the CRISPR-mediated homologous recombination technique in myogenic C2C12 cells to generate homozygous K176R knock-in cells (PGAM2). Compared with wild-type (WT) C2C12 cells, PGAM2 C2C12 cells exhibited impaired myogenic differentiation, as indicated by decreased differentiation and fusion indexes. Furthermore, the results of glycolytic and mitochondrial stress assays with the XF96 Extracellular Flux analyzer revealed a reduced proton efflux rate (PER), glycolytic PER (glycoPER), extracellular acidification rate (ECAR), and oxygen consumption rate (OCR) in PGAM2 C2C12 cells, both at baseline and in response to stress. Impaired mitochondrial function was also observed in PGAM2 P19 cells, a carcinoma cell line. These findings indicate that the PGAM2-K176R mutation impaired glycolysis and mitochondrial function. Gene ontology term analysis of RNA sequencing data further revealed that several downregulated genes in PGAM2 C2C12 cells were associated with muscle differentiation/development/contraction programs. Finally, PGAM2 with either of two naturally occurring missense mutations linked to GSDX, E89A (conversion of glutamic acid 89 to alanine) or R90W (conversion of arginine 90 to tryptophan), exhibited reduced Phosphoglycerate mutase 2 sumoylation. Thus, sumoylation is an important mechanism that mediates Phosphoglycerate mutase 2 activity and is potentially implicated in Phosphoglycerate mutase 2 mutation-linked disease in humans.
PubMed: 36589741
DOI: 10.3389/fcell.2022.1052363 -
ACS Medicinal Chemistry Letters Jun 2022
PubMed: 35707145
DOI: 10.1021/acsmedchemlett.2c00181 -
International Journal of Molecular... Dec 2020Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every hepatic disease. Necroptosis is a common form of... (Review)
Review
Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every hepatic disease. Necroptosis is a common form of programmed cell death in the liver. Necroptosis can be activated by ligands of death receptors, which then interact with receptor-interactive protein kinases 1 (RIPK1). RIPK1 mediates receptor interacting receptor-interactive protein kinases 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) and necrosome formation. Regarding the molecular mechanisms of mitochondrial-mediated necroptosis, the RIPK1/RIPK3/MLKL necrosome complex can enhance oxidative respiration and generate reactive oxygen species, which can be a crucial factor in the susceptibility of cells to necroptosis. The necrosome complex is also linked to mitochondrial components such as phosphoglycerate mutase family member 5 (PGAM5), metabolic enzymes in the mitochondrial matrix, mitochondrial permeability protein, and cyclophilin D. In this review, we focus on the role of mitochondria-mediated cell necroptosis in acute liver injury, chronic liver diseases, and hepatocellular carcinoma, and its possible translation into clinical applications.
Topics: Biomarkers; Disease Management; Disease Susceptibility; Gene Expression Regulation, Enzymologic; Humans; Liver Diseases; Mitochondria; Mitochondrial Proteins; Necroptosis; Phosphoprotein Phosphatases; Reactive Oxygen Species
PubMed: 33374660
DOI: 10.3390/ijms22010066 -
Cell Cycle (Georgetown, Tex.) Jun 2019Mature human erythrocytes are dependent on anerobic glycolysis, i.e. catabolism (oxidation) of one glucose molecule to produce two ATP and two lactate molecules.... (Review)
Review
Mature human erythrocytes are dependent on anerobic glycolysis, i.e. catabolism (oxidation) of one glucose molecule to produce two ATP and two lactate molecules. Proliferating tumor cells mimick mature human erythrocytes to glycolytically generate two ATP molecules. They deliberately avoid or switch off their respiration, i.e. tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) machinery and consequently dispense with the production of additional 36 ATP molecules from one glucose molecule. This phenomenon is named aerobic glycolysis or Warburg effect. The present review deals with the fate of a glucose molecule after entering a mature human erythrocyte or a proliferating tumor cell and describes why it is useful for a proliferating tumor cell to imitate a mature erythrocyte. Blood consisting of plasma and cellular components (99% of the cells are erythrocytes) may be regarded as a mobile organ, constantly exercising a direct interaction with other organs. Therefore, the use of drugs, which influences the biological activity of erythrocytes, has an immediate effect on the entire organism. : TCA: tricarboxylic acid cycle; OXPHOS: oxidative phosphorylation; GSH: reduced state of glutathione; NFκB: Nuclear factor of kappa B; PKB (Akt): protein kinase B; NOS: nitric oxide synthase; IgG: immune globulin G; HS: hydrogen sulfide; slanDCs: Human 6-sulfo LacNAc-expressing dendritic cells; IL-8: interleukin-8; LPS: lipopolysaccharide; ROS: reactive oxygen species; PPP: pentose phosphate pathway; NADPH: nicotinamide adenine dinucleotide phosphate hydrogen; R5P: ribose-5-phophate; NAD: nicotinamide adenine dinucleotide; FAD: flavin adenine dinucleotide; O: superoxide anion; G6P: glucose 6-phosphate; HbO: Oxyhemoglobin; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GAP: glyceraldehyde-3-phosphate; 1,3-BPG: 1,3-bis-phosphoglycerate; 2,3-BPG: 2,3-bisphosphoglycerte; PGAM1: phosphoglycerate mutase 1; 3-PG: 3-phosphoglycerate; 2-PG: 2-phosphoglycerate; MIPP1: Multiple inositol polyphosphate phosphatase; mTORC1: mammalian target of rapamycin complex 1; Ru5P: ribulose 5-phosphate; ox-PPP: oxidative branch of pentose phosphate pathway; PGK: phosphoglycerate kinase; IFN-γ: interferon-γ; LDH: lactate dehydrogenase; STAT3: signal transducer and activator of transcription 3; Rheb: Ras homolog enriched in Brain; HO: hydrogen peroxide; ROOH: lipid peroxide; SOD: superoxide dismutase; MRC: mitochondrial respiratory chain; MbFe-O: methmyoglobin; RNR: ribonucleotide reductase; PRPP: phosphoribosylpyrophosphate; PP: pyrophosphate; GSSG: oxidized state of glutathione; non-ox-PPP: non-oxidative branch of pentose phosphate pathway; RPI: ribose-5-phosphate isomerase; RPE: ribulose 5-phosphate 3-epimerase; X5P: xylulose 5-phosphate; TK: transketolase; TA: transaldolase; F6P: fructose-6-phosphate; AR2: aldose reductase 2; SD: sorbitol dehydrogenase; HK: hexokinase; MG: mehtylglyoxal; DHAP: dihydroxyacetone phosphate; TILs: tumor-infiltrating lymphocytes; MCTs: monocarboxylate transporters; pHi: intracellular pH; Hif-1α: hypoxia-induced factor 1; NHE1: sodium/H (Na/H) antiporter 1; V-ATPase: vacuolar-type proton ATPase; CAIX: carbonic anhydrase; CO: carbon dioxide; HCO: bicarbonate; NBC: sodium/bicarbonate (Na/HCO) symporter; pHe: extracellular pH; GLUT-1: glucose transporter 1; PGK-1: phosphoglycerate kinase 1.
Topics: Carcinogenesis; Cell Proliferation; Erythrocytes; Glucose; Glycolysis; Humans; Neoplasms
PubMed: 31154896
DOI: 10.1080/15384101.2019.1618125 -
Microbes and Infection 2020Stenotrophomonas maltophilia biofilm formation is of increasing medical concern, particularly for lung infections. However, the molecular mechanisms facilitating the...
Stenotrophomonas maltophilia biofilm formation is of increasing medical concern, particularly for lung infections. However, the molecular mechanisms facilitating the biofilm lifestyle in S. maltophilia are poorly understood. We generated and screened a transposon mutant library for mutations that lead to altered biofilm formation compared to wild type. One of these mutations, in the gene for glycolytic enzyme phosphoglycerate mutase (gpmA), resulted in impaired attachment on abiotic and biotic surfaces. As adherence to a surface is the initial step in biofilm developmental processes, our results reveal a unique factor that could affect S. maltophilia biofilm initiation and, possibly, subsequent development.
Topics: Bacterial Adhesion; Bacterial Proteins; Biofilms; Cells, Cultured; Epithelial Cells; Humans; Mutation; Phosphoglycerate Mutase; Plastics; Stenotrophomonas maltophilia
PubMed: 31430538
DOI: 10.1016/j.micinf.2019.08.001 -
IScience May 2022Brown adipose tissue (BAT) is a metabolically active organ that contributes to the thermogenic response to cold exposure. In addition, other thermogenic cells termed...
Brown adipose tissue (BAT) is a metabolically active organ that contributes to the thermogenic response to cold exposure. In addition, other thermogenic cells termed beige adipocytes are generated in white adipose tissue (WAT) by cold exposure. Although activation of brown/beige adipose tissue is associated with mobilization of both glucose and lipids, few studies have focused on the role of glycolytic enzymes in regulating adipose tissue function. We generated mouse models with specific deletion of the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) from adipose tissue. Deletion of Pgam1 from both BAT and WAT promoted whitening of BAT with beiging of visceral WAT, whereas deletion of Pgam1 from BAT alone led to whitening of BAT without beiging of WAT. Our results demonstrate a potential role of glycolytic enzymes in beiging of visceral WAT and suggest that PGAM1 would be a novel therapeutic target in obesity and diabetes.
PubMed: 35521515
DOI: 10.1016/j.isci.2022.104268 -
World Journal of Clinical Cases May 2022Drugs targeting mitochondria can induce mitophagy and restrain proliferation in colorectal cancer (CRC) cells. Phosphoglycerate mutase family member 5 (PGAM5) activates...
BACKGROUND
Drugs targeting mitochondria can induce mitophagy and restrain proliferation in colorectal cancer (CRC) cells. Phosphoglycerate mutase family member 5 (PGAM5) activates serine/threonine PTEN-induced putative kinase 1/Parkin pathway-mediated mitophagy. However, there are few studies on the clinical and prognostic significance of expression of PGAM5 protein and mitophagy-related protein Parkin in patients.
AIM
To assess the clinical significance of PGAM5 and Parkin proteins, as biomarkers for diagnosis and prognosis of CRC, by studying their expression in advanced CRC tissues and their association with clinicopathological parameters.
METHODS
The expression of PGAM5 and Parkin in CRC tissues from 100 patients was determined by immunohistochemistry. Each case was evaluated by using a combined scoring method based on signal intensity staining (scored 0-3) and the proportion of positively stained cancer cells (scored 0-4). The final staining score was calculated as the intensity score multiplied by the proportion score. Specimens were categorized as either high or low expression according to the Youden index, and the association between the expression of PGAM5 or Parkin and clinicopathological factors was ascertained. Additionally, we employed western blot to measure PGAM5 and Parkin protein expression in six matched pairs of CRC and adjacent non-tumor tissues.
RESULTS
Immunohistochemical and western blot findings showed that both PGAM5 and Parkin protein expression in tumor tissues was significantly higher than that in the adjacent tissues: PGAM5 and Parkin were mainly expressed in the cytoplasm of colonic epithelial cells. PGAM5 and Parkin protein levels were significantly positively correlated in advanced CRC tissues. Moreover, reduced Parkin protein expression was an independent prognostic factor for overall survival and progression-free survival in CRC patients as evinced by multivariate analysis.
CONCLUSION
The expression of PGAM5 protein and mitophagy-related protein Parkin has diagnostic significance for CRC and may become new biomarkers. Parkin may be a potential marker for the survival of CRC patients.
PubMed: 35663086
DOI: 10.12998/wjcc.v10.i14.4368 -
Aging Cell Feb 2022Decline in ovarian reserve with aging is associated with reduced fertility and the development of metabolic abnormalities. Once mitochondrial homeostasis is imbalanced,...
Decline in ovarian reserve with aging is associated with reduced fertility and the development of metabolic abnormalities. Once mitochondrial homeostasis is imbalanced, it may lead to poor reproductive cell quality and aging. However, Phosphoglycerate translocase 5 (PGAM5), located in the mitochondrial membrane, is associated with necroptosis, apoptosis, and mitophagy, although the underlying mechanisms associated with ovarian aging remain unknown. Therefore, we attempted to uncover whether the high phosphoglycerate mutant enzyme family member 5 (PGAM5) expression is associated with female infertility in cumulus cells, and aims to find out the underlying mechanism of action of PGAM5. We found that PGAM5 is highly expressed and positively associated with aging, and has the potential to help maintain and regulate mitochondrial dynamics and metabolic reprogramming in aging granulosa cells, ovaries of aged female mice, and elderly patients. PGAM5 undergoes activation in the aging group and translocated to the outer membrane of mitochondria, co-regulating DRP1; thereby increasing mitochondrial fission. A significant reduction in the quality of mitochondria in the aging group, a serious imbalance, and a significant reduction in energy, causing metabolism shift toward glycolysis, were also reported. Since PGAM5 is eliminated, the mitochondrial function and metabolism of aging cells are partially reversed. A total of 70 patients undergoing in vitro fertilization (IVF) treatment were recruited in this clinical study. The high expression of PGAM5 in the cumulus cells is negatively correlated with the pregnancy rate of infertile patients. Hence, PGAM5 has immense potential to be used as a diagnostic marker.
Topics: Aged; Animals; Family; Female; Humans; Mice; Mitochondrial Dynamics; Mitochondrial Proteins; Oocytes; Phosphoglycerate Mutase; Phosphoprotein Phosphatases; Pregnancy
PubMed: 34995407
DOI: 10.1111/acel.13546 -
Diagnostics (Basel, Switzerland) Jan 2021Fibromyalgia (FM) is a highly prevalent syndrome that impairs the quality of life of the patients; however, its diagnosis is complex and mainly centered on pain... (Review)
Review
Fibromyalgia (FM) is a highly prevalent syndrome that impairs the quality of life of the patients; however, its diagnosis is complex and mainly centered on pain symptoms. The study of salivary biomarkers has proven highly useful for the diagnosis and prognosis of numerous diseases. The objective of this review was to gather published data on the utilization of salivary biomarkers to facilitate and complement the diagnosis of FM. Salivary biomarkers used in FM diagnosis include cortisol; calgranulin; and the enzymes α-amylase, transaldolase, and phosphoglycerate mutase. Increased serum levels of C-reactive protein, cytokines interleukin 1-β, interleukin 6, interleukin 8, interleukin 10, interleukin 17, tumor necrosis factor α, and various chemokines may serve as salivary biomarkers, given observations of their increased serum levels in patients with FM. Further research is warranted to study in depth the role and performance of biomarkers currently used in FM diagnosis/prognosis and to identify novel salivary biomarkers for this disease.
PubMed: 33401557
DOI: 10.3390/diagnostics11010063