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Signal Transduction and Targeted Therapy Sep 2022The current understanding of lactate extends from its origins as a byproduct of glycolysis to its role in tumor metabolism, as identified by studies on the Warburg... (Review)
Review
The current understanding of lactate extends from its origins as a byproduct of glycolysis to its role in tumor metabolism, as identified by studies on the Warburg effect. The lactate shuttle hypothesis suggests that lactate plays an important role as a bridging signaling molecule that coordinates signaling among different cells, organs and tissues. Lactylation is a posttranslational modification initially reported by Professor Yingming Zhao's research group in 2019. Subsequent studies confirmed that lactylation is a vital component of lactate function and is involved in tumor proliferation, neural excitation, inflammation and other biological processes. An indispensable substance for various physiological cellular functions, lactate plays a regulatory role in different aspects of energy metabolism and signal transduction. Therefore, a comprehensive review and summary of lactate is presented to clarify the role of lactate in disease and to provide a reference and direction for future research. This review offers a systematic overview of lactate homeostasis and its roles in physiological and pathological processes, as well as a comprehensive overview of the effects of lactylation in various diseases, particularly inflammation and cancer.
Topics: Glycolysis; Homeostasis; Humans; Inflammation; Lactic Acid; Neoplasms
PubMed: 36050306
DOI: 10.1038/s41392-022-01151-3 -
Molecular Cancer Dec 2013Altered energy metabolism is a biochemical fingerprint of cancer cells that represents one of the "hallmarks of cancer". This metabolic phenotype is characterized by... (Review)
Review
Altered energy metabolism is a biochemical fingerprint of cancer cells that represents one of the "hallmarks of cancer". This metabolic phenotype is characterized by preferential dependence on glycolysis (the process of conversion of glucose into pyruvate followed by lactate production) for energy production in an oxygen-independent manner. Although glycolysis is less efficient than oxidative phosphorylation in the net yield of adenosine triphosphate (ATP), cancer cells adapt to this mathematical disadvantage by increased glucose up-take, which in turn facilitates a higher rate of glycolysis. Apart from providing cellular energy, the metabolic intermediates of glycolysis also play a pivotal role in macromolecular biosynthesis, thus conferring selective advantage to cancer cells under diminished nutrient supply. Accumulating data also indicate that intracellular ATP is a critical determinant of chemoresistance. Under hypoxic conditions where glycolysis remains the predominant energy producing pathway sensitizing cancer cells would require intracellular depletion of ATP by inhibition of glycolysis. Together, the oncogenic regulation of glycolysis and multifaceted roles of glycolytic components underscore the biological significance of tumor glycolysis. Thus targeting glycolysis remains attractive for therapeutic intervention. Several preclinical investigations have indeed demonstrated the effectiveness of this therapeutic approach thereby supporting its scientific rationale. Recent reviews have provided a wealth of information on the biochemical targets of glycolysis and their inhibitors. The objective of this review is to present the most recent research on the cancer-specific role of glycolytic enzymes including their non-glycolytic functions in order to explore the potential for therapeutic opportunities. Further, we discuss the translational potential of emerging drug candidates in light of technical advances in treatment modalities such as image-guided targeted delivery of cancer therapeutics.
Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Enzymes; Glycolysis; Humans; Molecular Targeted Therapy; Neoplasms
PubMed: 24298908
DOI: 10.1186/1476-4598-12-152 -
Cell Metabolism Apr 2018Once thought to be a waste product of anaerobic metabolism, lactate is now known to form continuously under aerobic conditions. Shuttling between producer and consumer... (Review)
Review
Once thought to be a waste product of anaerobic metabolism, lactate is now known to form continuously under aerobic conditions. Shuttling between producer and consumer cells fulfills at least three purposes for lactate: (1) a major energy source, (2) the major gluconeogenic precursor, and (3) a signaling molecule. "Lactate shuttle" (LS) concepts describe the roles of lactate in delivery of oxidative and gluconeogenic substrates as well as in cell signaling. In medicine, it has long been recognized that the elevation of blood lactate correlates with illness or injury severity. However, with lactate shuttle theory in mind, some clinicians are now appreciating lactatemia as a "strain" and not a "stress" biomarker. In fact, clinical studies are utilizing lactate to treat pro-inflammatory conditions and to deliver optimal fuel for working muscles in sports medicine. The above, as well as historic and recent studies of lactate metabolism and shuttling, are discussed in the following review.
Topics: Animals; Brain; Gluconeogenesis; Glycolysis; Humans; Lactic Acid; Oxidation-Reduction
PubMed: 29617642
DOI: 10.1016/j.cmet.2018.03.008 -
International Journal of Biological... 2022Emerging evidence suggests that metabolic adaptation is a vital hallmark and prerequisite for macrophage phenotype transition. Pyruvate kinase M2 (PKM2) is an essential...
Emerging evidence suggests that metabolic adaptation is a vital hallmark and prerequisite for macrophage phenotype transition. Pyruvate kinase M2 (PKM2) is an essential molecular determinant of metabolic adaptions in pro-inflammatory macrophages. Post-translational modifications play a central role in the regulation of PKM2. However, doubt remains on whether lactylation in PKM2 exists and how lactylation modulates the function of PKM2. For the first time, our study reports that lactate inhibits the Warburg effect by activating PKM2, promoting the transition of pro-inflammatory macrophages towards a reparative phenotype. We identify PKM2 as a lactylation substrate and confirm that lactylation occurs mainly at the K62 site. We find that lactate increases the lactylation level of PKM2, which inhibits its tetramer-to-dimer transition, promoting its pyruvate kinase activity and reducing nuclear distribution. In short, our study reports a novel post-translational modification type in PKM2 and clarifies its potential role in regulating inflammatory metabolic adaptation in pro-inflammatory macrophages.
Topics: Pyruvate Kinase; Macrophages; Glycolysis; Phosphorylation; Lactates
PubMed: 36439872
DOI: 10.7150/ijbs.75434 -
Annual Review of Physiology Feb 2021Pulmonary arterial hypertension (PAH) is characterized by impaired regulation of pulmonary hemodynamics and vascular growth. Alterations of metabolism and bioenergetics... (Review)
Review
Pulmonary arterial hypertension (PAH) is characterized by impaired regulation of pulmonary hemodynamics and vascular growth. Alterations of metabolism and bioenergetics are increasingly recognized as universal hallmarks of PAH, as metabolic abnormalities are identified in lungs and hearts of patients, animal models of the disease, and cells derived from lungs of patients. Mitochondria are the primary organelle critically mediating the complex and integrative metabolic pathways in bioenergetics, biosynthetic pathways, and cell signaling. Here, we review the alterations in metabolic pathways that are linked to the pathologic vascular phenotype of PAH, including abnormalities in glycolysis and glucose oxidation, fatty acid oxidation, glutaminolysis, arginine metabolism, one-carbon metabolism, the reducing and oxidizing cell environment, and the tricarboxylic acid cycle, as well as the effects of PAH-associated nuclear and mitochondrial mutations on metabolism. Understanding of the metabolic mechanisms underlying PAH provides important knowledge for the design of new therapeutics for treatment of patients.
Topics: Animals; Glycolysis; Humans; Hypertension, Pulmonary; Lung; Metabolic Networks and Pathways; Mitochondria
PubMed: 33566674
DOI: 10.1146/annurev-physiol-031620-123956 -
Journal of Cell Science Oct 2021Hypoxia inhibits the tricarboxylic acid (TCA) cycle and leaves glycolysis as the primary metabolic pathway responsible for converting glucose into usable energy.... (Review)
Review
Hypoxia inhibits the tricarboxylic acid (TCA) cycle and leaves glycolysis as the primary metabolic pathway responsible for converting glucose into usable energy. However, the mechanisms that compensate for this loss in energy production due to TCA cycle inactivation remain poorly understood. Glycolysis enzymes are typically diffuse and soluble in the cytoplasm under normoxic conditions. In contrast, recent studies have revealed dynamic compartmentalization of glycolysis enzymes in response to hypoxic stress in yeast, C. elegans and mammalian cells. These messenger ribonucleoprotein (mRNP) structures, termed glycolytic (G) bodies in yeast, lack membrane enclosure and display properties of phase-separated biomolecular condensates. Disruption of condensate formation correlates with defects such as impaired synaptic function in C. elegans neurons and decreased glucose flux in yeast. Concentrating glycolysis enzymes into condensates may lead to their functioning as 'metabolons' that enhance rates of glucose utilization for increased energy production. Besides condensates, glycolysis enzymes functionally associate in other organisms and specific tissues through protein-protein interactions and membrane association. However, as discussed in this Review, the functional consequences of coalescing glycolytic machinery are only just beginning to be revealed. Through ongoing studies, we anticipate the physiological importance of metabolic regulation mediated by the compartmentalization of glycolysis enzymes will continue to emerge.
Topics: Animals; Caenorhabditis elegans; Citric Acid Cycle; Glucose; Glycolysis; Saccharomyces cerevisiae
PubMed: 34668544
DOI: 10.1242/jcs.258469 -
The Journal of Biological Chemistry 2021
Topics: Gluconeogenesis; Glucose; Glycolysis
PubMed: 33410396
DOI: 10.1016/j.jbc.2020.100016 -
Nature Reviews. Drug Discovery Sep 2020The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by... (Review)
Review
The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner - a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.
Topics: Aging; Animals; Brain; Energy Metabolism; Glycolysis; Humans; Neurodegenerative Diseases; Oxidative Phosphorylation
PubMed: 32709961
DOI: 10.1038/s41573-020-0072-x -
International Journal of Molecular... Jan 2023Cancer cells undergo metabolic reprogramming and switch to a 'glycolysis-dominant' metabolic profile to promote their survival and meet their requirements for energy and... (Review)
Review
Cancer cells undergo metabolic reprogramming and switch to a 'glycolysis-dominant' metabolic profile to promote their survival and meet their requirements for energy and macromolecules. This phenomenon, also known as the 'Warburg effect,' provides a survival advantage to the cancer cells and make the tumor environment more pro-cancerous. Additionally, the increased glycolytic dependence also promotes chemo/radio resistance. A similar switch to a glycolytic metabolic profile is also shown by the immune cells in the tumor microenvironment, inducing a competition between the cancer cells and the tumor-infiltrating cells over nutrients. Several recent studies have shown that targeting the enhanced glycolysis in cancer cells is a promising strategy to make them more susceptible to treatment with other conventional treatment modalities, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, and photodynamic therapy. Although several targeting strategies have been developed and several of them are in different stages of pre-clinical and clinical evaluation, there is still a lack of effective strategies to specifically target cancer cell glycolysis to improve treatment efficacy. Herein, we have reviewed our current understanding of the role of metabolic reprogramming in cancer cells and how targeting this phenomenon could be a potential strategy to improve the efficacy of conventional cancer therapy.
Topics: Humans; Glycolysis; Neoplasms; Tumor Microenvironment
PubMed: 36768924
DOI: 10.3390/ijms24032606 -
Cell Reports Apr 2023Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show...
Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.
Topics: Humans; Female; Mice; Animals; Glycolysis; Energy Metabolism; Magnetic Resonance Imaging; Neurons; Glucose
PubMed: 37027294
DOI: 10.1016/j.celrep.2023.112335