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Cell Stem Cell Jul 2022Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation; however, the mechanism remains incompletely understood. Here, we demonstrated...
Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation; however, the mechanism remains incompletely understood. Here, we demonstrated that homeostatic HSCs exhibited high amino acid (AA) catabolism to reduce cellular AA levels, which activated the GCN2-eIF2α axis, a protein synthesis inhibitory checkpoint to restrain protein synthesis for maintenance. Furthermore, upon proliferation conditions, HSCs enhanced mitochondrial oxidative phosphorylation (OXPHOS) for higher energy production but decreased AA catabolism to accumulate cellular AAs, which inactivated the GCN2-eIF2α axis to increase protein synthesis and coupled with proteotoxic stress. Importantly, GCN2 deletion impaired HSC function in repopulation and regeneration. Mechanistically, GCN2 maintained proteostasis and inhibited Src-mediated AKT activation to repress mitochondrial OXPHOS in HSCs. Moreover, the glycolytic metabolite, NAD precursor nicotinamide riboside (NR), accelerated AA catabolism to activate GCN2 and sustain the long-term function of HSCs. Overall, our study uncovered direct links between metabolic alterations and translation control in HSCs during homeostasis and proliferation.
Topics: Amino Acids; Eukaryotic Initiation Factor-2; Hematopoietic Stem Cells; Oxidative Phosphorylation; Phosphorylation; Proteostasis
PubMed: 35803229
DOI: 10.1016/j.stem.2022.06.004 -
Nature Cell Biology Jul 2018Although classically appreciated for their role as the powerhouse of the cell, the metabolic functions of mitochondria reach far beyond bioenergetics. In this Review, we... (Review)
Review
Although classically appreciated for their role as the powerhouse of the cell, the metabolic functions of mitochondria reach far beyond bioenergetics. In this Review, we discuss how mitochondria catabolize nutrients for energy, generate biosynthetic precursors for macromolecules, compartmentalize metabolites for the maintenance of redox homeostasis and function as hubs for metabolic waste management. We address the importance of these roles in both normal physiology and in disease.
Topics: Animals; Biological Transport; Cell Survival; Energy Metabolism; Homeostasis; Humans; Mitochondria; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 29950572
DOI: 10.1038/s41556-018-0124-1 -
Physiological Reviews Oct 2022For nearly 50 years the proximal tubule (PT) has been known to reabsorb, process, and either catabolize or transcytose albumin from the glomerular filtrate. Innovative... (Review)
Review
For nearly 50 years the proximal tubule (PT) has been known to reabsorb, process, and either catabolize or transcytose albumin from the glomerular filtrate. Innovative techniques and approaches have provided insights into these processes. Several genetic diseases, nonselective PT cell defects, chronic kidney disease (CKD), and acute PT injury lead to significant albuminuria, reaching nephrotic range. Albumin is also known to stimulate PT injury cascades. Thus, the mechanisms of albumin reabsorption, catabolism, and transcytosis are being reexamined with the use of techniques that allow for novel molecular and cellular discoveries. Megalin, a scavenger receptor, cubilin, amnionless, and Dab2 form a nonselective multireceptor complex that mediates albumin binding and uptake and directs proteins for lysosomal degradation after endocytosis. Albumin transcytosis is mediated by a pH-dependent binding affinity to the neonatal Fc receptor (FcRn) in the endosomal compartments. This reclamation pathway rescues albumin from urinary losses and cellular catabolism, extending its serum half-life. Albumin that has been altered by oxidation, glycation, or carbamylation or because of other bound ligands that do not bind to FcRn traffics to the lysosome. This molecular sorting mechanism reclaims physiological albumin and eliminates potentially toxic albumin. The clinical importance of PT albumin metabolism has also increased as albumin is now being used to bind therapeutic agents to extend their half-life and minimize filtration and kidney injury. The purpose of this review is to update and integrate evolving information regarding the reabsorption and processing of albumin by proximal tubule cells including discussion of genetic disorders and therapeutic considerations.
Topics: Albumins; Biological Transport; Endocytosis; Humans; Kidney Tubules, Proximal
PubMed: 35378997
DOI: 10.1152/physrev.00014.2021 -
Critical Care Medicine Feb 2017To provide an appraisal of the evolving paradigms in the pathophysiology of sepsis and propose the evolution of a new phenotype of critically ill patients, its potential...
OBJECTIVES
To provide an appraisal of the evolving paradigms in the pathophysiology of sepsis and propose the evolution of a new phenotype of critically ill patients, its potential underlying mechanism, and its implications for the future of sepsis management and research.
DESIGN
Literature search using PubMed, MEDLINE, EMBASE, and Google Scholar.
MEASUREMENTS AND MAIN RESULTS
Sepsis remains one of the most debilitating and expensive illnesses, and its prevalence is not declining. What is changing is our definition(s), its clinical course, and how we manage the septic patient. Once thought to be predominantly a syndrome of over exuberant inflammation, sepsis is now recognized as a syndrome of aberrant host protective immunity. Earlier recognition and compliance with treatment bundles has fortunately led to a decline in multiple organ failure and in-hospital mortality. Unfortunately, more and more sepsis patients, especially the aged, are suffering chronic critical illness, rarely fully recover, and often experience an indolent death. Patients with chronic critical illness often exhibit "a persistent inflammation-immunosuppression and catabolism syndrome," and it is proposed here that this state of persisting inflammation, immunosuppression and catabolism contributes to many of these adverse clinical outcomes. The underlying cause of inflammation-immunosuppression and catabolism syndrome is currently unknown, but there is increasing evidence that altered myelopoiesis, reduced effector T-cell function, and expansion of immature myeloid-derived suppressor cells are all contributory.
CONCLUSIONS
Although newer therapeutic interventions are targeting the inflammatory, the immunosuppressive, and the protein catabolic responses individually, successful treatment of the septic patient with chronic critical illness and persistent inflammation-immunosuppression and catabolism syndrome may require a more complementary approach.
Topics: Biomedical Research; Chronic Disease; Critical Care; Critical Illness; Humans; Immune Tolerance; Inflammation; Metabolism; Sepsis; Syndrome
PubMed: 27632674
DOI: 10.1097/CCM.0000000000002074 -
Cell Reports May 2023Organelle interactions play a significant role in compartmentalizing metabolism and signaling. Lipid droplets (LDs) interact with numerous organelles, including...
Organelle interactions play a significant role in compartmentalizing metabolism and signaling. Lipid droplets (LDs) interact with numerous organelles, including mitochondria, which is largely assumed to facilitate lipid transfer and catabolism. However, quantitative proteomics of hepatic peridroplet mitochondria (PDM) and cytosolic mitochondria (CM) reveals that CM are enriched in proteins comprising various oxidative metabolism pathways, whereas PDM are enriched in proteins involved in lipid anabolism. Isotope tracing and super-resolution imaging confirms that fatty acids (FAs) are selectively trafficked to and oxidized in CM during fasting. In contrast, PDM facilitate FA esterification and LD expansion in nutrient-replete medium. Additionally, mitochondrion-associated membranes (MAM) around PDM and CM differ in their proteomes and ability to support distinct lipid metabolic pathways. We conclude that CM and CM-MAM support lipid catabolic pathways, whereas PDM and PDM-MAM allow hepatocytes to efficiently store excess lipids in LDs to prevent lipotoxicity.
Topics: Fatty Acids; Lipid Metabolism; Liver; Lipid Droplets; Proteome
PubMed: 37104088
DOI: 10.1016/j.celrep.2023.112435 -
Molecules (Basel, Switzerland) Nov 2017Melatonin is catabolized both enzymatically and nonenzymatically. Nonenzymatic processes mediated by free radicals, singlet oxygen, other reactive intermediates such as... (Review)
Review
Melatonin is catabolized both enzymatically and nonenzymatically. Nonenzymatic processes mediated by free radicals, singlet oxygen, other reactive intermediates such as HOCl and peroxynitrite, or pseudoenzymatic mechanisms are not species- or tissue-specific, but vary considerably in their extent. Higher rates of nonenzymatic melatonin metabolism can be expected upon UV exposure, e.g., in plants and in the human skin. Additionally, melatonin is more strongly nonenzymatically degraded at sites of inflammation. Typical products are several hydroxylated derivatives of melatonin and ¹-acetyl-²-formyl-5-methoxykynuramine (AFMK). Most of these products are also formed by enzymatic catalysis. Considerable taxon- and site-specific differences are observed in the main enzymatic routes of catabolism. Formation of 6-hydroxymelatonin by cytochrome P subforms are prevailing in vertebrates, predominantly in the liver, but also in the brain. In pineal gland and non-mammalian retina, deacetylation to 5-methoxytryptamine (5-MT) plays a certain role. This pathway is quantitatively prevalent in dinoflagellates, in which 5-MT induces cyst formation and is further converted to 5-methoxyindole-3-acetic acid, an end product released to the water. In plants, the major route is catalyzed by melatonin 2-hydroxylase, whose product is tautomerized to 3-acetamidoethyl-3-hydroxy-5-methoxyindolin-2-one (AMIO), which exceeds the levels of melatonin. Formation and properties of various secondary products are discussed.
Topics: Acetylation; Animals; Catalysis; Humans; Hydroxylation; Melatonin; Metabolic Networks and Pathways
PubMed: 29160833
DOI: 10.3390/molecules22112015 -
American Society of Clinical Oncology... Jan 2019Cancer cells are known to have distinct metabolic characteristics compared with normal cells, given the catabolic and anabolic demands of increased cell growth and... (Review)
Review
Cancer cells are known to have distinct metabolic characteristics compared with normal cells, given the catabolic and anabolic demands of increased cell growth and proliferation. This altered metabolism in cancer cells imbues differential dependencies, and substantial effort has been invested in developing therapeutic strategies to exploit these potential vulnerabilities. Parallel to these efforts has been a growing appreciation for the presence of notable intratumoral metabolic heterogeneity. Although many novel agents are showing some promising results in targeting specific metabolic processes, the challenge moving forward will be to develop combination strategies to address the aforementioned metabolic heterogeneity and its interplay with both epigenetic and immune factors in the tumor microenvironment. In this review, we discuss recent developments in targeting tumor catabolism, lipid biosynthesis, glycolysis, and the citric acid cycle as well as efforts to combine these approaches with immunotherapy.
Topics: Disease Management; Energy Metabolism; Humans; Metabolic Networks and Pathways; Molecular Targeted Therapy; Neoplasms
PubMed: 31099667
DOI: 10.1200/EDBK_238499 -
Lipids in Health and Disease Jun 2017Lipids are essential building blocks synthesized by complex molecular pathways and deposited as lipid droplets (LDs) in cells. LDs are evolutionary conserved organelles... (Review)
Review
Lipids are essential building blocks synthesized by complex molecular pathways and deposited as lipid droplets (LDs) in cells. LDs are evolutionary conserved organelles found in almost all organisms, from bacteria to mammals. They are composed of a hydrophobic neutral lipid core surrounding by a phospholipid monolayer membrane with various decorating proteins. Degradation of LDs provide metabolic energy for divergent cellular processes such as membrane synthesis and molecular signaling. Lipolysis and autophagy are two main catabolic pathways of LDs, which regulate lipid metabolism and, thereby, closely engaged in many pathological conditons. In this review, we first provide an overview of the current knowledge on the structural properties and the biogenesis of LDs. We further focus on the recent findings of their catabolic mechanism by lipolysis and autophagy as well as their connection ragarding the regulation and function. Moreover, we discuss the relevance of LDs and their catabolism-dependent pathophysiological conditions.
Topics: Animals; Autophagy; Humans; Lipid Droplets; Lipid Metabolism; Lipolysis; Phospholipids
PubMed: 28662670
DOI: 10.1186/s12944-017-0521-7 -
Autophagy Jan 2017Macroautophagy/autophagy is a key catabolic process, essential for maintaining cellular homeostasis and survival through the removal and recycling of unwanted cellular... (Review)
Review
Macroautophagy/autophagy is a key catabolic process, essential for maintaining cellular homeostasis and survival through the removal and recycling of unwanted cellular material. Emerging evidence has revealed intricate connections between the RNA and autophagy research fields. While a majority of studies have focused on protein, lipid and carbohydrate catabolism via autophagy, accumulating data supports the view that several types of RNA and associated ribonucleoprotein complexes are specifically recruited to phagophores (precursors to autophagosomes) and subsequently degraded in the lysosome/vacuole. Moreover, recent studies have revealed a substantial number of novel autophagy regulators with RNA-related functions, indicating roles for RNA and associated proteins not only as cargo, but also as regulators of this process. In this review, we discuss widespread evidence of RNA catabolism via autophagy in yeast, plants and animals, reviewing the molecular mechanisms and biological importance in normal physiology, stress and disease. In addition, we explore emerging evidence of core autophagy regulation mediated by RNA-binding proteins and noncoding RNAs, and point to gaps in our current knowledge of the connection between RNA and autophagy. Finally, we discuss the pathological implications of RNA-protein aggregation, primarily in the context of neurodegenerative disease.
Topics: Animals; Arabidopsis; Autophagy; Carbohydrate Metabolism; Drosophila melanogaster; Genome; HEK293 Cells; HeLa Cells; Humans; Lipid Metabolism; Lysosomes; Metabolism; Neurodegenerative Diseases; Neurons; Proteins; RNA; RNA, Long Noncoding; RNA, Transfer; RNA, Viral; RNA-Binding Proteins; Tetrahymena; Vacuoles; Zebrafish
PubMed: 27715443
DOI: 10.1080/15548627.2016.1222992 -
Environmental Microbiology Oct 2019The biology literature is rife with misleading information on how to quantify catabolic reaction energetics. The principal misconception is that the sign and value of... (Review)
Review
The biology literature is rife with misleading information on how to quantify catabolic reaction energetics. The principal misconception is that the sign and value of the standard Gibbs energy ( ) define the direction and energy yield of a reaction; they do not. is one part of the actual Gibbs energy of a reaction (ΔG ), with a second part accounting for deviations from the standard composition. It is also frequently assumed that applies only to 25 °C and 1 bar; it does not. is a function of temperature and pressure. Here, we review how to determine ΔG as a function of temperature, pressure and chemical composition for microbial catabolic reactions, including a discussion of the effects of ionic strength on ΔG and highlighting the large effects when multi-valent ions are part of the reaction. We also calculate ΔG for five example catabolisms at specific environmental conditions: aerobic respiration of glucose in freshwater, anaerobic respiration of acetate in marine sediment, hydrogenotrophic methanogenesis in a laboratory batch reactor, anaerobic ammonia oxidation in a wastewater reactor and aerobic pyrite oxidation in acid mine drainage. These examples serve as templates to determine the energy yields of other catabolic reactions at environmentally relevant conditions.
Topics: Bacteria; Ecosystem; Energy Metabolism; Environmental Microbiology; Geologic Sediments; Water Microbiology
PubMed: 31403238
DOI: 10.1111/1462-2920.14778