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Cell Metabolism Jul 2019Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can account for up to 50% of some... (Review)
Review
Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can account for up to 50% of some solid neoplasms. Most often, TAMs support disease progression and resistance to therapy by providing malignant cells with trophic and nutritional support. However, TAMs can mediate antineoplastic effects, especially in response to pharmacological agents that boost their phagocytic and oxidative functions. Thus, TAMs and their impact on the overall metabolic profile of the TME have a major influence on tumor progression and resistance to therapy, de facto constituting promising targets for the development of novel anticancer agents. Here, we discuss the metabolic circuitries whereby TAMs condition the TME to support tumor growth and how such pathways can be therapeutically targeted.
Topics: Animals; Humans; Immunotherapy; Macrophages; Oxidative Phosphorylation; Tumor Microenvironment
PubMed: 31269428
DOI: 10.1016/j.cmet.2019.06.001 -
Redox Biology Oct 2020The mitochondrial electron transport chain utilizes a series of electron transfer reactions to generate cellular ATP through oxidative phosphorylation. A consequence of... (Review)
Review
The mitochondrial electron transport chain utilizes a series of electron transfer reactions to generate cellular ATP through oxidative phosphorylation. A consequence of electron transfer is the generation of reactive oxygen species (ROS), which contributes to both homeostatic signaling as well as oxidative stress during pathology. In this graphical review we provide an overview of oxidative phosphorylation and its inter-relationship with ROS production by the electron transport chain. We also outline traditional and novel translational methodology for assessing mitochondrial energetics in health and disease.
Topics: Electron Transport; Mitochondrial Membranes; Oxidants; Oxidative Phosphorylation; Oxidative Stress; Reactive Oxygen Species
PubMed: 32811789
DOI: 10.1016/j.redox.2020.101674 -
Immunity Mar 2023In vitro studies have associated oxidative phosphorylation (OXPHOS) with anti-inflammatory macrophages, whereas pro-inflammatory macrophages rely on glycolysis....
In vitro studies have associated oxidative phosphorylation (OXPHOS) with anti-inflammatory macrophages, whereas pro-inflammatory macrophages rely on glycolysis. However, the metabolic needs of macrophages in tissues (TMFs) to fulfill their homeostatic activities are incompletely understood. Here, we identified OXPHOS as the highest discriminating process among TMFs from different organs in homeostasis by analysis of RNA-seq data in both humans and mice. Impairing OXPHOS in TMFs via Tfam deletion differentially affected TMF populations. Tfam deletion resulted in reduction of alveolar macrophages (AMs) due to impaired lipid-handling capacity, leading to increased cholesterol content and cellular stress, causing cell-cycle arrest in vivo. In obesity, Tfam depletion selectively ablated pro-inflammatory lipid-handling white adipose tissue macrophages (WAT-MFs), thus preventing insulin resistance and hepatosteatosis. Hence, OXPHOS, rather than glycolysis, distinguishes TMF populations and is critical for the maintenance of TMFs with a high lipid-handling activity, including pro-inflammatory WAT-MFs. This could provide a selective therapeutic targeting tool.
Topics: Humans; Mice; Animals; Oxidative Phosphorylation; Inflammation; Macrophages; Homeostasis; Lipids; Adipose Tissue
PubMed: 36738738
DOI: 10.1016/j.immuni.2023.01.011 -
Disease Models & Mechanisms Jun 2021Mitochondria are organelles with vital functions in almost all eukaryotic cells. Often described as the cellular 'powerhouses' due to their essential role in aerobic... (Review)
Review
Mitochondria are organelles with vital functions in almost all eukaryotic cells. Often described as the cellular 'powerhouses' due to their essential role in aerobic oxidative phosphorylation, mitochondria perform many other essential functions beyond energy production. As signaling organelles, mitochondria communicate with the nucleus and other organelles to help maintain cellular homeostasis, allow cellular adaptation to diverse stresses, and help steer cell fate decisions during development. Mitochondria have taken center stage in the research of normal and pathological processes, including normal tissue homeostasis and metabolism, neurodegeneration, immunity and infectious diseases. The central role that mitochondria assume within cells is evidenced by the broad impact of mitochondrial diseases, caused by defects in either mitochondrial or nuclear genes encoding for mitochondrial proteins, on different organ systems. In this Review, we will provide the reader with a foundation of the mitochondrial 'hardware', the mitochondrion itself, with its specific dynamics, quality control mechanisms and cross-organelle communication, including its roles as a driver of an innate immune response, all with a focus on development, disease and aging. We will further discuss how mitochondrial DNA is inherited, how its mutation affects cell and organismal fitness, and current therapeutic approaches for mitochondrial diseases in both model organisms and humans.
Topics: Animals; Homeostasis; Humans; Mitochondria; Mitochondrial Diseases; Oxidative Phosphorylation
PubMed: 34114603
DOI: 10.1242/dmm.048912 -
Ageing Research Reviews Mar 2021Osteoarthritis (OA) is a degenerative joint disease characterized by low-grade inflammation and high levels of clinical heterogeneity. Aberrant chondrocyte metabolism is... (Review)
Review
Osteoarthritis (OA) is a degenerative joint disease characterized by low-grade inflammation and high levels of clinical heterogeneity. Aberrant chondrocyte metabolism is a response to changes in the inflammatory microenvironment and may play a key role in cartilage degeneration and OA progression. Under conditions of environmental stress, chondrocytes tend to adapt their metabolism to microenvironmental changes by shifting from one metabolic pathway to another, for example from oxidative phosphorylation to glycolysis. Similar changes occur in other joint cells, including synoviocytes. Switching between these pathways is implicated in metabolic alterations that involve mitochondrial dysfunction, enhanced anaerobic glycolysis, and altered lipid and amino acid metabolism. The shift between oxidative phosphorylation and glycolysis is mainly regulated by the AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) pathways. Chondrocyte metabolic changes are likely to be a feature of different OA phenotypes. Determining the role of chondrocyte metabolism in OA has revealed key features of disease pathogenesis. Future research should place greater emphasis on immunometabolism and altered metabolic pathways as a means to understand the pathophysiology of age-related OA. This knowledge will advance the development of new drugs against therapeutic targets of metabolic significance.
Topics: Cartilage, Articular; Chondrocytes; Humans; Osteoarthritis; Oxidative Phosphorylation; Oxidative Stress
PubMed: 33383189
DOI: 10.1016/j.arr.2020.101249 -
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 -
Biochimica Et Biophysica Acta.... Nov 2020In living cells, growth is the result of coupling between substrate catabolism and multiple metabolic processes that take place during net biomass formation and... (Review)
Review
In living cells, growth is the result of coupling between substrate catabolism and multiple metabolic processes that take place during net biomass formation and maintenance processes. During growth, both ATP/ADP and NADH/NAD molecules play a key role. Cell energy metabolism hence refers to metabolic pathways involved in ATP synthesis linked to NADH turnover. Two main pathways are thus involved in cell energy metabolism: glycolysis/fermentation and oxidative phosphorylation. Glycolysis and mitochondrial oxidative phosphorylation are intertwined through thermodynamic and kinetic constraints that are reviewed herein. Further, our current knowledge of short-term and long term regulation of cell energy metabolism will be reviewed using examples such as the Crabtree and the Warburg effect.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Cell Physiological Phenomena; Energy Metabolism; Glycolysis; Kinetics; NAD; Oxidative Phosphorylation
PubMed: 32717222
DOI: 10.1016/j.bbabio.2020.148276 -
Cell Metabolism Dec 2014Metformin is currently the first-line drug treatment for type 2 diabetes. Besides its glucose-lowering effect, there is interest in actions of the drug of potential... (Review)
Review
Metformin is currently the first-line drug treatment for type 2 diabetes. Besides its glucose-lowering effect, there is interest in actions of the drug of potential relevance to cardiovascular diseases and cancer. However, the underlying mechanisms of action remain elusive. Convincing data place energy metabolism at the center of metformin's mechanism of action in diabetes and may also be of importance in cardiovascular diseases and cancer. Metformin-induced activation of the energy-sensor AMPK is well documented, but may not account for all actions of the drug. Here, we summarize current knowledge about the different AMPK-dependent and AMPK-independent mechanisms underlying metformin action.
Topics: AMP-Activated Protein Kinases; Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Hypoglycemic Agents; Metformin; Oxidative Phosphorylation
PubMed: 25456737
DOI: 10.1016/j.cmet.2014.09.018 -
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 -
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