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Physiological Reviews Jul 2021Cells metabolize nutrients for biosynthetic and bioenergetic needs to fuel growth and proliferation. The uptake of nutrients from the environment and their intracellular... (Review)
Review
Cells metabolize nutrients for biosynthetic and bioenergetic needs to fuel growth and proliferation. The uptake of nutrients from the environment and their intracellular metabolism is a highly controlled process that involves cross talk between growth signaling and metabolic pathways. Despite constant fluctuations in nutrient availability and environmental signals, normal cells restore metabolic homeostasis to maintain cellular functions and prevent disease. A central signaling molecule that integrates growth with metabolism is the mechanistic target of rapamycin (mTOR). mTOR is a protein kinase that responds to levels of nutrients and growth signals. mTOR forms two protein complexes, mTORC1, which is sensitive to rapamycin, and mTORC2, which is not directly inhibited by this drug. Rapamycin has facilitated the discovery of the various functions of mTORC1 in metabolism. Genetic models that disrupt either mTORC1 or mTORC2 have expanded our knowledge of their cellular, tissue, as well as systemic functions in metabolism. Nevertheless, our knowledge of the regulation and functions of mTORC2, particularly in metabolism, has lagged behind. Since mTOR is an important target for cancer, aging, and other metabolism-related pathologies, understanding the distinct and overlapping regulation and functions of the two mTOR complexes is vital for the development of more effective therapeutic strategies. This review discusses the key discoveries and recent findings on the regulation and metabolic functions of the mTOR complexes. We highlight findings from cancer models but also discuss other examples of the mTOR-mediated metabolic reprogramming occurring in stem and immune cells, type 2 diabetes/obesity, neurodegenerative disorders, and aging.
Topics: Animals; Glycolysis; Humans; Lipid Metabolism; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Signal Transduction
PubMed: 33599151
DOI: 10.1152/physrev.00026.2020 -
Experimental & Molecular Medicine Sep 2020As knowledge of cell metabolism has advanced, glutamine has been considered an important amino acid that supplies carbon and nitrogen to fuel biosynthesis. A recent... (Review)
Review
As knowledge of cell metabolism has advanced, glutamine has been considered an important amino acid that supplies carbon and nitrogen to fuel biosynthesis. A recent study provided a new perspective on mitochondrial glutamine metabolism, offering mechanistic insights into metabolic adaptation during tumor hypoxia, the emergence of drug resistance, and glutaminolysis-induced metabolic reprogramming and presenting metabolic strategies to target glutamine metabolism in cancer cells. In this review, we introduce the various biosynthetic and bioenergetic roles of glutamine based on the compartmentalization of glutamine metabolism to explain why cells exhibit metabolic reliance on glutamine. Additionally, we examined whether glutamine derivatives contribute to epigenetic regulation associated with tumorigenesis. In addition, in discussing glutamine transporters, we propose a metabolic target for therapeutic intervention in cancer.
Topics: Animals; Cell Transformation, Neoplastic; Disease Susceptibility; Energy Metabolism; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Glutamine; Humans; Metabolic Networks and Pathways; Metabolome; Metabolomics; Neoplasms; Oxidation-Reduction; Signal Transduction
PubMed: 32943735
DOI: 10.1038/s12276-020-00504-8 -
Nature Metabolism Nov 2021The perception that intracellular lipolysis is a straightforward process that releases fatty acids from fat stores in adipose tissue to generate energy has experienced... (Review)
Review
The perception that intracellular lipolysis is a straightforward process that releases fatty acids from fat stores in adipose tissue to generate energy has experienced major revisions over the last two decades. The discovery of new lipolytic enzymes and coregulators, the demonstration that lipophagy and lysosomal lipolysis contribute to the degradation of cellular lipid stores and the characterization of numerous factors and signalling pathways that regulate lipid hydrolysis on transcriptional and post-transcriptional levels have revolutionized our understanding of lipolysis. In this review, we focus on the mechanisms that facilitate intracellular fatty-acid mobilization, drawing on canonical and noncanonical enzymatic pathways. We summarize how intracellular lipolysis affects lipid-mediated signalling, metabolic regulation and energy homeostasis in multiple organs. Finally, we examine how these processes affect pathogenesis and how lipolysis may be targeted to potentially prevent or treat various diseases.
Topics: Adipose Tissue; Animals; Biomarkers; Disease Management; Disease Susceptibility; Energy Metabolism; Fatty Acids; Gene Expression Regulation, Enzymologic; Humans; Lipid Mobilization; Lipolysis; Metabolic Networks and Pathways; Molecular Targeted Therapy; Protein Processing, Post-Translational; Triglycerides
PubMed: 34799702
DOI: 10.1038/s42255-021-00493-6 -
Cell Metabolism Sep 2019Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using...
Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using metabolic profiling, we found that exposure to amyloid-β triggers acute microglial inflammation accompanied by metabolic reprogramming from oxidative phosphorylation to glycolysis. It was dependent on the mTOR-HIF-1α pathway. However, once activated, microglia reached a chronic tolerant phase as a result of broad defects in energy metabolisms and subsequently diminished immune responses, including cytokine secretion and phagocytosis. Using genome-wide RNA sequencing and multiphoton microscopy techniques, we further identified metabolically defective microglia in 5XFAD mice, an AD mouse model. Finally, we showed that metabolic boosting with recombinant interferon-γ treatment reversed the defective glycolytic metabolism and inflammatory functions of microglia, thereby mitigating the AD pathology of 5XFAD mice. Collectively, metabolic reprogramming is crucial for microglial functions in AD, and modulating metabolism might be a new therapeutic strategy for AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line; Cytokines; Disease Models, Animal; Female; Gene Expression Regulation; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interferon-gamma; Male; Mice; Mice, Inbred ICR; Mice, Transgenic; Microglia; Oxidative Phosphorylation; Phagocytosis; Recombinant Proteins; TOR Serine-Threonine Kinases
PubMed: 31257151
DOI: 10.1016/j.cmet.2019.06.005 -
Neurochemical Research Oct 2019Post-translational modifications (PTMs) are important regulators of protein function, and integrate metabolism with physiological and pathological processes.... (Review)
Review
Post-translational modifications (PTMs) are important regulators of protein function, and integrate metabolism with physiological and pathological processes. Phosphorylation and acetylation are particularly well studied PTMs. A relatively recently discovered novel PTM is succinylation in which metabolically derived succinyl CoA modifies protein lysine groups. Succinylation causes a protein charge flip from positive to negative and a relatively large increase in mass compared to other PTMs. Hundreds of protein succinylation sites are present in proteins of multiple tissues and species, and the significance is being actively investigated. The few completed studies demonstrate that succinylation alters rates of enzymes and pathways, especially mitochondrial metabolic pathways. Thus, succinylation provides an elegant and efficient mechanism to coordinate metabolism and signaling by utilizing metabolic intermediates as sensors to regulate metabolism. Even though the brain is one of the most metabolically active organs, an understanding of the role succinylation in the nervous system is largely unknown. Data from other tissues and other PTMs suggest that succinylation provides a coupling between metabolism and protein function in the nervous system and in neurological diseases. This review provides a new insight into metabolism in neurological diseases and suggests that the drug development for these diseases requires a better understanding of succinylation and de-succinylation in the brain and other tissues.
Topics: Acyl Coenzyme A; Animals; Humans; Lysine; Metabolic Networks and Pathways; Mitochondria; Protein Processing, Post-Translational; Proteome
PubMed: 30903449
DOI: 10.1007/s11064-019-02780-x -
Cancer Biology & Medicine Feb 2020Since triple-negative breast cancer (TNBC) was first defined over a decade ago, increasing studies have focused on its genetic and molecular characteristics. Patients... (Review)
Review
Since triple-negative breast cancer (TNBC) was first defined over a decade ago, increasing studies have focused on its genetic and molecular characteristics. Patients diagnosed with TNBC, compared to those diagnosed with other breast cancer subtypes, have relatively poor outcomes due to high tumor aggressiveness and lack of targeted treatment. Metabolic reprogramming, an emerging hallmark of cancer, is hijacked by TNBC to fulfill bioenergetic and biosynthetic demands; maintain the redox balance; and further promote oncogenic signaling, cell proliferation, and metastasis. Understanding the mechanisms of metabolic remodeling may guide the design of metabolic strategies for the effective intervention of TNBC. Here, we review the metabolic reprogramming of glycolysis, oxidative phosphorylation, amino acid metabolism, lipid metabolism, and other branched pathways in TNBC and explore opportunities for new biomarkers, imaging modalities, and metabolically targeted therapies.
Topics: Amino Acids; Antineoplastic Agents; Biomarkers, Tumor; Female; Humans; Lipid Metabolism; Molecular Targeted Therapy; Oxidative Phosphorylation; Triple Negative Breast Neoplasms; Warburg Effect, Oncologic
PubMed: 32296576
DOI: 10.20892/j.issn.2095-3941.2019.0210 -
International Journal of Molecular... Jul 2019As a major component of cell membrane lipids, Arachidonic acid (AA), being a major component of the cell membrane lipid content, is mainly metabolized by three kinds of... (Review)
Review
As a major component of cell membrane lipids, Arachidonic acid (AA), being a major component of the cell membrane lipid content, is mainly metabolized by three kinds of enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Based on these three metabolic pathways, AA could be converted into various metabolites that trigger different inflammatory responses. In the kidney, prostaglandins (PG), thromboxane (Tx), leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) are the major metabolites generated from AA. An increased level of prostaglandins (PGs), TxA and leukotriene B4 (LTB) results in inflammatory damage to the kidney. Moreover, the LTB-leukotriene B4 receptor 1 (BLT1) axis participates in the acute kidney injury via mediating the recruitment of renal neutrophils. In addition, AA can regulate renal ion transport through 19-hydroxystilbenetetraenoic acid (19-HETE) and 20-HETE, both of which are produced by cytochrome P450 monooxygenase. Epoxyeicosatrienoic acids (EETs) generated by the CYP450 enzyme also plays a paramount role in the kidney damage during the inflammation process. For example, 14 and 15-EET mitigated ischemia/reperfusion-caused renal tubular epithelial cell damage. Many drug candidates that target the AA metabolism pathways are being developed to treat kidney inflammation. These observations support an extraordinary interest in a wide range of studies on drug interventions aiming to control AA metabolism and kidney inflammation.
Topics: Animals; Arachidonic Acid; Biomarkers; Disease Susceptibility; Humans; Lipid Metabolism; Metabolic Networks and Pathways; Molecular Targeted Therapy; Nephritis; Signal Transduction
PubMed: 31357612
DOI: 10.3390/ijms20153683 -
Cells Sep 2021In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is... (Review)
Review
In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.
Topics: Adaptation, Physiological; Animals; Cell Hypoxia; Humans; Hypoxia-Inducible Factor 1; Neoplasms; Signal Transduction
PubMed: 34572020
DOI: 10.3390/cells10092371 -
Drug Metabolism Reviews Aug 2019Lysergic acid diethylamide (LSD) is the most potent hallucinogen known and its pharmacological effect results from stimulation of central serotonin receptors (5-HT).... (Review)
Review
Lysergic acid diethylamide (LSD) is the most potent hallucinogen known and its pharmacological effect results from stimulation of central serotonin receptors (5-HT). Since LSD is seen as physiologically safe compound with low toxicity, its use in therapeutics has been renewed during the last few years. This review aims to discuss LSD metabolism, by presenting all metabolites as well as clinical and toxicological relevance. LSD is rapidly and extensively metabolized into inactive metabolites; whose detection window is higher than parent compound. The metabolite 2-oxo-3-hydroxy LSD is the major human metabolite, which detection and quantification is important for clinical and forensic toxicology. Indeed, information about LSD pharmacokinetics in humans is limited and for this reason, more research studies are needed.
Topics: Animals; Gastric Absorption; Humans; Lysergic Acid Diethylamide; Oral Mucosal Absorption; Serotonin Receptor Agonists; Tissue Distribution
PubMed: 31266388
DOI: 10.1080/03602532.2019.1638931 -
Nutrients Oct 2023Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost.... (Review)
Review
Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost. The Warburg hypothesis states that cancer cells have an altered cell metabolism towards anaerobic glycolysis. Given this metabolic reprogramming in cancer cells, it is possible to target cancers metabolically by depriving them of glucose. In addition to dietary and lifestyle modifications which work on tumors metabolically, there are a panoply of nutritional supplements and repurposed drugs associated with cancer prevention and better treatment outcomes. These interventions and their evidentiary basis are covered in the latter half of this review to guide future cancer treatment.
Topics: Humans; Neoplasms; Glycolysis; Energy Metabolism; Treatment Outcome
PubMed: 37836529
DOI: 10.3390/nu15194245