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Nature Communications Oct 2023Metabolic reprogramming is a hallmark of the immune cells in response to inflammatory stimuli. This metabolic process involves a switch from oxidative phosphorylation...
Metabolic reprogramming is a hallmark of the immune cells in response to inflammatory stimuli. This metabolic process involves a switch from oxidative phosphorylation (OXPHOS) to glycolysis or alterations in other metabolic pathways. However, most of the experimental findings have been acquired in murine immune cells, and little is known about the metabolic reprogramming of human microglia. In this study, we investigate the transcriptomic, proteomic, and metabolic profiles of mouse and iPSC-derived human microglia challenged with the TLR4 agonist LPS. We demonstrate that both species display a metabolic shift and an overall increased glycolytic gene signature in response to LPS treatment. The metabolic reprogramming is characterized by the upregulation of hexokinases in mouse microglia and phosphofructokinases in human microglia. This study provides a direct comparison of metabolism between mouse and human microglia, highlighting the species-specific pathways involved in immunometabolism and the importance of considering these differences in translational research.
Topics: Animals; Mice; Humans; Microglia; Lipopolysaccharides; Proteomics; Oxidative Phosphorylation; Glycolysis
PubMed: 37833292
DOI: 10.1038/s41467-023-42096-7 -
Signal Transduction and Targeted Therapy Oct 2020Metabolic reprogramming is reported to be one of the hallmarks of cancer, which is an adaptive mechanism by which fast-growing cancer cells adapt to their increasing... (Review)
Review
Metabolic reprogramming is reported to be one of the hallmarks of cancer, which is an adaptive mechanism by which fast-growing cancer cells adapt to their increasing energy demands. Recently, extracellular vesicles (EVs) known as exosomes have been recognized as crucial signaling mediators in regulating the tumor microenvironment (TME). Meanwhile, the TME is a highly heterogeneous ecosystem incorporating cancer cells, fibroblasts, adipocytes, endothelial cells, mesenchymal stem cells, and extracellular matrix. Accumulated evidence indicates that exosomes may transfer biologically functional molecules to the recipient cells, which facilitate cancer progression, angiogenesis, metastasis, drug resistance, and immunosuppression by reprogramming the metabolism of cancer cells and their surrounding stromal cells. In this review, we present the role of exosomes in the TME and the underlying mechanism of how exosomes exacerbate tumor development through metabolic reprogramming. In addition, we will also discuss the potential role of exosomes targeting metabolic process as biomarkers for tumor diagnosis and prognosis, and exosomes-mediated metabolic reprogramming as potential targets for cancer therapy. Furthermore, a better understanding of the link between exosomes and metabolic reprogramming, and their impact on cancer progression, would provide novel insights for cancer prevention and treatment in the future.
Topics: Animals; Biological Transport, Active; Cellular Reprogramming; Drug Resistance, Neoplasm; Exosomes; Humans; Immunosuppression Therapy; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 33077737
DOI: 10.1038/s41392-020-00359-5 -
The Biochemical Journal Mar 2020Fatty acids (FAs) are stored safely in the form of triacylglycerol (TAG) in lipid droplet (LD) organelles by professional storage cells called adipocytes. These lipids... (Review)
Review
Fatty acids (FAs) are stored safely in the form of triacylglycerol (TAG) in lipid droplet (LD) organelles by professional storage cells called adipocytes. These lipids are mobilized during adipocyte lipolysis, the fundamental process of hydrolyzing TAG to FAs for internal or systemic energy use. Our understanding of adipocyte lipolysis has greatly increased over the past 50 years from a basic enzymatic process to a dynamic regulatory one, involving the assembly and disassembly of protein complexes on the surface of LDs. These dynamic interactions are regulated by hormonal signals such as catecholamines and insulin which have opposing effects on lipolysis. Upon stimulation, patatin-like phospholipase domain containing 2 (PNPLA2)/adipocyte triglyceride lipase (ATGL), the rate limiting enzyme for TAG hydrolysis, is activated by the interaction with its co-activator, alpha/beta hydrolase domain-containing protein 5 (ABHD5), which is normally bound to perilipin 1 (PLIN1). Recently identified negative regulators of lipolysis include G0/G1 switch gene 2 (G0S2) and PNPLA3 which interact with PNPLA2 and ABHD5, respectively. This review focuses on the dynamic protein-protein interactions involved in lipolysis and discusses some of the emerging concepts in the control of lipolysis that include allosteric regulation and protein turnover. Furthermore, recent research demonstrates that many of the proteins involved in adipocyte lipolysis are multifunctional enzymes and that lipolysis can mediate homeostatic metabolic signals at both the cellular and whole-body level to promote inter-organ communication. Finally, adipocyte lipolysis is involved in various diseases such as cancer, type 2 diabetes and fatty liver disease, and targeting adipocyte lipolysis is of therapeutic interest.
Topics: Adipocytes; Animals; Diabetes Mellitus; Energy Metabolism; Enzyme Inhibitors; Humans; Lipolysis; Neoplasms; Non-alcoholic Fatty Liver Disease; Protein Interaction Domains and Motifs
PubMed: 32168372
DOI: 10.1042/BCJ20190468 -
Developmental Cell Mar 2015Fatty acids (FAs) provide cellular energy under starvation, yet how they mobilize and move into mitochondria in starved cells, driving oxidative respiration, is unclear....
Fatty acids (FAs) provide cellular energy under starvation, yet how they mobilize and move into mitochondria in starved cells, driving oxidative respiration, is unclear. Here, we clarify this process by visualizing FA trafficking with a fluorescent FA probe. The labeled FA accumulated in lipid droplets (LDs) in well-fed cells but moved from LDs into mitochondria when cells were starved. Autophagy in starved cells replenished LDs with FAs, increasing LD number over time. Cytoplasmic lipases removed FAs from LDs, enabling their transfer into mitochondria. This required mitochondria to be highly fused and localized near LDs. When mitochondrial fusion was prevented in starved cells, FAs neither homogeneously distributed within mitochondria nor became efficiently metabolized. Instead, FAs reassociated with LDs and fluxed into neighboring cells. Thus, FAs engage in complex trafficking itineraries regulated by cytoplasmic lipases, autophagy, and mitochondrial fusion dynamics, ensuring maximum oxidative metabolism and avoidance of FA toxicity in starved cells.
Topics: Animals; Autophagy; Biological Transport; Cell Line; Fatty Acids; Fibroblasts; Fluorescent Dyes; Lipase; Lipid Droplets; Lipid Metabolism; Lipolysis; Mice; Mitochondria; Mitochondrial Dynamics; Oxidation-Reduction; Respiration; Starvation
PubMed: 25752962
DOI: 10.1016/j.devcel.2015.01.029 -
Science Advances Mar 2023Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully...
Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Despite its metabolic key function, the role of MPC in NSPCs has not been addressed. We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic ablation in vitro and in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify an important pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation.
Topics: Animals; Mice; Neurogenesis; Neurons; Biological Transport; Neural Stem Cells; Mitochondria; Monocarboxylic Acid Transporters
PubMed: 36857455
DOI: 10.1126/sciadv.add5220 -
American Journal of Physiology. Heart... Mar 2019Cardiovascular-related pathologies are the single leading cause of death in patients with chronic kidney disease (CKD). Previously, we found that a 5/6th nephrectomy...
Cardiovascular-related pathologies are the single leading cause of death in patients with chronic kidney disease (CKD). Previously, we found that a 5/6th nephrectomy model of CKD leads to an upregulation of miR-21-5p in the left ventricle, targeting peroxisome proliferator-activated receptor-α and altering the expression of numerous transcripts involved with fatty acid oxidation and glycolysis. In the present study, we evaluated the potential for knockdown or overexpression of miR-21-5p to regulate lipid content, lipid peroxidation, and mitochondrial respiration in H9C2 cells. Cells were transfected with anti-miR-21-5p (40 nM), pre-miR-21-5p (20 nM), or the appropriate scrambled oligonucleotide controls before lipid treatment in culture or as part of the Agilent Seahorse XF fatty acid oxidation assay. Overexpression of miR-21-5p attenuated the lipid-induced increase in cellular lipid content, whereas suppression of miR-21-5p augmented it. The abundance of malondialdehyde, a product of lipid peroxidation, was significantly increased with lipid treatment in control cells but attenuated in pre-miR-21-5p-transfected cells. This suggests that miR-21-5p reduces oxidative stress. The cellular oxygen consumption rate (OCR) was increased in both pre-miR-21-5p- and anti-miR-21-5p-transfected cells. Levels of intracellular ATP were significantly higher in anti-mR-21-5p-transfected cells. Pre-miR-21-5p blocked additional increases in OCR in response to etomoxir and palmitic acid. Conversely, anti-miR-21-5p-transfected cells exhibited reduced OCR with both etomoxir and palmitic acid, and the glycolytic capacity was concomitantly reduced. Together, these results indicate that overexpression of miR-21-5p attenuates both lipid content and lipid peroxidation in H9C2 cells. This likely occurs by reducing cellular lipid uptake and utilization, shifting cellular metabolism toward reliance on the glycolytic pathway. NEW & NOTEWORTHY Both overexpression and suppression of miR-21-5p augment basal and maximal mitochondrial respiration. Our data suggest that reliance on glycolytic and fatty acid oxidation pathways can be modulated by the abundance of miR-21-5p within the cell. miR-21-5p regulation of mitochondrial respiration can be modulated by extracellular lipids.
Topics: Animals; Cell Line; Fatty Acids; Glycolysis; Lipid Metabolism; Lipid Peroxidation; Malondialdehyde; MicroRNAs; Mitochondria; Myoblasts; Oxidation-Reduction; Oxidative Stress; Oxygen Consumption; Rats
PubMed: 30657727
DOI: 10.1152/ajpheart.00538.2017 -
Cells Mar 2020Our common knowledge on oxidative stress has evolved substantially over the years, being focused mostly on the fundamental chemical reactions and the most relevant...
Our common knowledge on oxidative stress has evolved substantially over the years, being focused mostly on the fundamental chemical reactions and the most relevant chemical species involved in human pathophysiology of oxidative stress-associated diseases. Thus, reactive oxygen species and reactive nitrogen species (ROS and RNS) were identified as key players in initiating, mediating, and regulating the cellular and biochemical complexity of oxidative stress either as physiological (acting pro-hormetic) or as pathogenic (causing destructive vicious circles) processes. The papers published in this particular Special Issue of show an impressive range on the pathophysiological relevance of ROS and RNS, including the relevance of second messengers of free radicals like 4-hydroxynonenal, allowing us to assume that the future will reveal even more detailed mechanisms of their positive and negative effects that might improve the monitoring of major modern diseases, and aid the development of advanced integrative biomedical treatments.
Topics: Cells; Humans; Lipid Peroxidation; Oxidative Stress; Reactive Nitrogen Species; Reactive Oxygen Species; Toll-Like Receptors
PubMed: 32245147
DOI: 10.3390/cells9030767 -
Journal of Experimental & Clinical... Jan 2023Enolase 2 (ENO2) is a crucial glycolytic enzyme in cancer metabolic process and acts as a "moonlighting" protein to play various functions in diverse cellular processes...
BACKGROUND
Enolase 2 (ENO2) is a crucial glycolytic enzyme in cancer metabolic process and acts as a "moonlighting" protein to play various functions in diverse cellular processes unrelated to glycolysis. ENO2 is highly expressed in head and neck squamous cell carcinoma (HNSCC) tissues relative to normal tissues; however, its impact and underlying regulatory mechanisms in HNSCC malignancy remain unclear.
METHODS
Molecular alterations were examined by bioinformatics, qRT-PCR, western blotting, immunofluorescence, immunohistochemistry, immunoprecipitation, and ChIP-PCR assays. Metabolic changes were assessed by intracellular levels of ATP and glucose. Animal study was used to evaluate the therapeutic efficacy of the ENO inhibitor.
RESULTS
ENO2 is required for HNSCC cell proliferation and glycolysis, which, surprisingly, is partially achieved by controlling PKM2 protein stability and its nuclear translocation. Mechanistically, loss of ENO2 expression promotes PKM2 protein degradation via the ubiquitin-proteasome pathway and prevents the switch of cytoplasmic PKM2 to the nucleus by inactivating AKT signaling, leading to a blockade in PKM2-mediated glycolytic flux and CCND1-associated cell cycle progression. In addition, treatment with the ENO inhibitor AP-III-a4 significantly induces HNSCC remission in a preclinical mouse model.
CONCLUSION
Our work elucidates the signaling basis underlying ENO2-dependent HNSCC development, providing evidence to establish a novel ENO2-targeted therapy for treating HNSCC.
Topics: Animals; Mice; Cell Line, Tumor; Glycolysis; Head and Neck Neoplasms; Phosphopyruvate Hydratase; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Pyruvate Kinase
PubMed: 36588153
DOI: 10.1186/s13046-022-02574-0 -
Molecular Biology Reports Oct 2022Energy metabolism maintains the activation of intracellular and intercellular signal transduction, and plays a crucial role in immune response. Under environmental... (Review)
Review
Energy metabolism maintains the activation of intracellular and intercellular signal transduction, and plays a crucial role in immune response. Under environmental stimulation, immune cells change from resting to activation and trigger metabolic reprogramming. The immune system cells exhibit different metabolic characteristics when performing functions. The study of immune metabolism provides new insights into the function of immune cells, including how they differentiate, migrate and exert immune responses. Studies of immune cell energy metabolism are beginning to shed light on the metabolic mechanism of disease progression and reveal new ways to target inflammatory diseases such as autoimmune diseases, chronic viral infections, and cancer. Here, we discussed the relationship between immune cells and metabolism, and proposed the possibility of targeted metabolic process for disease treatment.
Topics: Autoimmune Diseases; Energy Metabolism; Humans; Immune System; Neoplasms; Signal Transduction
PubMed: 35696048
DOI: 10.1007/s11033-022-07474-2 -
Frontiers in Immunology 2021T cell metabolism is central to cell proliferation, survival, differentiation, and aberrations have been linked to the pathophysiology of systemic autoimmune diseases.... (Review)
Review
T cell metabolism is central to cell proliferation, survival, differentiation, and aberrations have been linked to the pathophysiology of systemic autoimmune diseases. Besides glycolysis and fatty acid oxidation/synthesis, amino acid metabolism is also crucial in T cell metabolism. It appears that each T cell subset favors a unique metabolic process and that metabolic reprogramming changes cell fate. Here, we review the mechanisms whereby amino acid transport and metabolism affects T cell activation, differentiation and function in T cells in the prototype systemic autoimmune disease systemic lupus erythematosus. New insights in amino acid handling by T cells should guide approaches to correct T cell abnormalities and disease pathology.
Topics: Amino Acid Transport Systems; Amino Acids; Animals; Autoimmunity; Energy Metabolism; Humans; Lupus Erythematosus, Systemic; Lymphocyte Activation; Phenotype; T-Lymphocytes
PubMed: 33692797
DOI: 10.3389/fimmu.2021.623844