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Science Immunology Jul 2023The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the... (Review)
Review
The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the ectonucleotidase CD73. The pro-inflammatory nucleotides adenosine triphosphate, nicotinamide adenine dinucleotide, and cyclic guanosine -monophosphate-AMP (cGAMP), which are produced in the tumor microenvironment (TME) during therapy-induced immunogenic cell death and activation of innate immune signaling, can be converted into AMP by ectonucleotidases CD39, CD38, and CD203a/ENPP1. Thus, ectonucleotidases shape the TME by converting immune-activating signals into an immunosuppressive one. Ectonucleotidases also hinder the ability of therapies including radiation therapy, which enhance the release of pro-inflammatory nucleotides in the extracellular milieu, to induce immune-mediated tumor rejection. Here, we review the immunosuppressive effects of adenosine and the role of different ectonucleotidases in modulating antitumor immune responses. We discuss emerging opportunities to target adenosine generation and/or its ability to signal via adenosine receptors expressed by immune and cancer cells in the context of combination immunotherapy and radiotherapy.
Topics: Humans; Neoplasms; Adenosine; Adenosine Triphosphate; Adenosine Monophosphate; DNA Damage; Tumor Microenvironment
PubMed: 37418547
DOI: 10.1126/sciimmunol.abq3015 -
Neurobiology of Disease Sep 2023Purinergic receptors (Rs) of the ATP/ADP, UTP/UDP (P2X, P2Y) and adenosine (A1, A2A)-sensitive classes broadly interfere with cognitive processes both under quasi normal... (Review)
Review
Purinergic receptors (Rs) of the ATP/ADP, UTP/UDP (P2X, P2Y) and adenosine (A1, A2A)-sensitive classes broadly interfere with cognitive processes both under quasi normal and disease conditions. During neurodegenerative illnesses, high concentrations of ATP are released from the damaged neuronal and non-neuronal cells of the brain; then, this ATP is enzymatically degraded to adenosine. Thus, the primary injury in neurodegenerative diseases appears to be caused by various protein aggregates on which a superimposed damage mediated by especially P2X7 and A2AR activation develops; this can be efficiently prevented by small molecular antagonists in animal models of the above diseases, or are mitigated in the respective knockout mice. Dementia is a leading symptom in Alzheimer's disease (AD), and accompanies Parkinson's disease (PD) and Huntington's disease (HD), especially in the advanced states of these illnesses. Animal experimentation suggests that P2X7 and A2ARs are also involved in a number of psychiatric diseases, such as major depressive disorder (MDD), obsessive compulsive behavior, and attention deficit hyperactivity disorder. In conclusion, small molecular antagonists of purinergic receptors are expected to supply us in the future with pharmaceuticals which are able to combat in a range of neurological/psychiatric diseases the accompanying cognitive deterioration.
Topics: Animals; Mice; Depressive Disorder, Major; Receptors, Purinergic; Adenosine; Adenosine Triphosphate; Nervous System Diseases; Cognition
PubMed: 37453562
DOI: 10.1016/j.nbd.2023.106229 -
Proceedings of the National Academy of... Jun 2023Many types of differentiated cells can reenter the cell cycle upon injury or stress. The underlying mechanisms are still poorly understood. Here, we investigated how...
Many types of differentiated cells can reenter the cell cycle upon injury or stress. The underlying mechanisms are still poorly understood. Here, we investigated how quiescent cells are reactivated using a zebrafish model, in which a population of differentiated epithelial cells are reactivated under a physiological context. A robust and sustained increase in mitochondrial membrane potential was observed in the reactivated cells. Genetic and pharmacological perturbations show that elevated mitochondrial metabolism and ATP synthesis are critical for cell reactivation. Further analyses showed that elevated mitochondrial metabolism increases mitochondrial ROS levels, which induces Sgk1 expression in the mitochondria. Genetic deletion and inhibition of Sgk1 in zebrafish abolished epithelial cell reactivation. Similarly, ROS-dependent mitochondrial expression of SGK1 promotes S phase entry in human breast cancer cells. Mechanistically, SGK1 coordinates mitochondrial activity with ATP synthesis by phosphorylating FF-ATP synthase. These findings suggest a conserved intramitochondrial signaling loop regulating epithelial cell renewal.
Topics: Animals; Humans; Reactive Oxygen Species; Zebrafish; Mitochondria; Epithelial Cells; Adenosine Triphosphate
PubMed: 37276417
DOI: 10.1073/pnas.2216310120 -
Advanced Science (Weinheim,... Sep 2023Liver metastasis is the most fatal event of colon cancer patients. Warburg effect has been long challenged by the fact of upregulated oxidative phosphorylation (OXPHOS),...
Liver metastasis is the most fatal event of colon cancer patients. Warburg effect has been long challenged by the fact of upregulated oxidative phosphorylation (OXPHOS), while its mechanism remains unclear. Here, metastasis-associated antigen 1 (MTA1) is identified as a newly identified adenosine triphosphate (ATP) synthase modulator by interacting with ATP synthase F1 subunit alpha (ATP5A), facilitates colon cancer liver metastasis by driving mitochondrial bioenergetic metabolism reprogramming, enhancing OXPHOS; therefore, modulating ATP synthase activity and downstream mTOR pathways. High-throughput screening of an anticancer drug shows MTA1 knockout increases the sensitivity of colon cancer to mitochondrial bioenergetic metabolism-targeted drugs and mTOR inhibitors. Inhibiting ATP5A enhances the sensitivity of liver-metastasized colon cancer to sirolimus in an MTA1-dependent manner. The therapeutic effects are verified in xenograft models and clinical cases. This research identifies a new modulator of mitochondrial bioenergetic reprogramming in cancer metastasis and reveals a new mechanism on upregulating mitochondrial OXPHOS as the reversal of Warburg effect in cancer metastasis is orchestrated.
Topics: Humans; Adenosine Triphosphate; Energy Metabolism; Oxidative Phosphorylation; Colonic Neoplasms; Liver Neoplasms
PubMed: 37442756
DOI: 10.1002/advs.202300756 -
Autophagy Jan 2024Omega-shaped domains of the endoplasmic reticulum, known as omegasomes, have been suggested to contribute to autophagosome biogenesis, although their exact function is...
Omega-shaped domains of the endoplasmic reticulum, known as omegasomes, have been suggested to contribute to autophagosome biogenesis, although their exact function is not known. Omegasomes are characterized by the presence of the double FYVE domain containing protein ZFYVE1/DFCP1, but it has remained a paradox that depletion of ZFYVE1 does not prevent bulk macroautophagy/autophagy. We recently showed that ZFYVE1 contains an N-terminal ATPase domain which dimerizes upon ATP binding. Mutations in the ATPase domain that inhibit ATP binding or hydrolysis do not prevent omegasome expansion and maturation. However, omegasome constriction is inhibited by these mutations, which results in an increased lifetime and thereby higher number of omegasomes. Interestingly, whereas knockout or mutations do not significantly affect bulk autophagy, selective autophagy of mitochondria, protein aggregates and micronuclei is inhibited. We propose that ATP binding and hydrolysis control the di- or multimerization state of ZFYVE1 which could provide the mechanochemical energy to drive large omegasome constriction and autophagosome completion.
Topics: Autophagy; Autophagosomes; Macroautophagy; Adenosine Triphosphatases; Adenosine Triphosphate
PubMed: 37722386
DOI: 10.1080/15548627.2023.2255967 -
International Journal of Molecular... Jun 2023Extensive evidence indicates that the activation of the P2X receptor (P2XR), an ATP-gated ion channel highly expressed in immune and brain cells, is strictly associated... (Review)
Review
Extensive evidence indicates that the activation of the P2X receptor (P2XR), an ATP-gated ion channel highly expressed in immune and brain cells, is strictly associated with the release of extracellular vesicles. Through this process, P2XR-expressing cells regulate non-classical protein secretion and transfer bioactive components to other cells, including misfolded proteins, participating in inflammatory and neurodegenerative diseases. In this review, we summarize and discuss the studies addressing the impact of P2XR activation on extracellular vesicle release and their activities.
Topics: Brain; Extracellular Vesicles; Receptors, Purinergic P2X7; Adenosine Triphosphate
PubMed: 37372953
DOI: 10.3390/ijms24129805 -
Comparative Biochemistry and... 2024Mitochondria serve several important roles in maintaining cellular homeostasis, including adenosine triphosphate (ATP) synthesis, apoptotic signalling, and regulation of... (Review)
Review
Mitochondria serve several important roles in maintaining cellular homeostasis, including adenosine triphosphate (ATP) synthesis, apoptotic signalling, and regulation of both reactive oxygen species (ROS) and calcium. Therefore, mitochondrial studies may reveal insights into metabolism at higher levels of physiological organization. The apparent complexity of mitochondrial function may be daunting to researchers new to mitochondrial physiology. This review is aimed, therefore, at such researchers to provide a brief, yet approachable overview of common techniques used to assess mitochondrial function. Here we discuss the use of high-resolution respirometry in mitochondrial experiments and common analytical platforms used for this technique. Next, we compare the use of common mitochondrial preparation techniques, including adherent cells, tissue homogenate, permeabilized fibers and isolated mitochondria. Finally, we outline additional techniques that can be used in tandem with high-resolution respirometry to assess additional aspects of mitochondrial metabolism, including ATP synthesis, calcium uptake, membrane potential and reactive oxygen species emission. We also include limitations to each of these techniques and outline recommendations for experimental design and interpretation. With a general understanding of methodologies commonly used to study mitochondrial physiology, experimenters may begin contributing to our understanding of this organelle, and how it affects other physiological phenotypes.
Topics: Animals; Adenosine Triphosphate; Calcium; Energy Metabolism; Mitochondria; Reactive Oxygen Species; Humans
PubMed: 38278207
DOI: 10.1016/j.cbpb.2024.110947 -
International Journal of Molecular... Oct 2023Adenosine, an immunosuppressive metabolite, is produced by adenosine triphosphate (ATP) released from dying or stressed cells and is found at high levels in the tumor... (Review)
Review
Adenosine, an immunosuppressive metabolite, is produced by adenosine triphosphate (ATP) released from dying or stressed cells and is found at high levels in the tumor microenvironment of most solid tumors. It mediates pro-tumor activities by inducing tumor cell proliferation, migration or invasion, tumor tissue angiogenesis, and chemoresistance. In addition, adenosine plays an important role in regulating anti-tumor immune responses and facilitating tumor immune escape. Adenosine receptors are broadly expressed by tumor-infiltrated immune cells, including suppressive tumor-associated macrophages and CD4 regulatory T cells, as well as effector CD4 T cells and CD8 cytotoxic T lymphocytes. Therefore, adenosine is indispensable in down-regulating anti-tumor immune responses in the tumor microenvironment and contributes to tumor progression. This review describes the current progress on the role of adenosine/adenosine receptor pathway in regulating the tumor-infiltrating immune cells that contribute to tumor immune evasion and aims to provide insights into adenosine-targeted tumor immunotherapy.
Topics: Humans; Adenosine; Tumor Microenvironment; Adenosine Triphosphate; Neoplasms; CD8-Positive T-Lymphocytes; T-Lymphocytes, Regulatory; 5'-Nucleotidase
PubMed: 37834375
DOI: 10.3390/ijms241914928 -
Biomedicine & Pharmacotherapy =... Sep 2023Adenosine is an endogenous nucleoside that regulates many physiological and pathological processes. It is derived from either the intracellular or extracellular... (Review)
Review
Adenosine is an endogenous nucleoside that regulates many physiological and pathological processes. It is derived from either the intracellular or extracellular dephosphorylation of adenosine triphosphate and interacts with cell-surface G-protein-coupled receptors. Adenosine plays a substantial role in protecting against cell damage in areas of increased tissue metabolism and preventing organ dysfunction in pathological states. Targeting adenosine metabolism and receptor signaling may be an effective therapeutic approach for human diseases, including cardiovascular and central nervous system disorders, rheumatoid arthritis, asthma, renal diseases, and cancer. Several lines of evidence have shown that many drugs exert their beneficial effects by modulating adenosine signaling pathways but this knowledge urgently needs to be summarized, and most importantly, actualized. The present review collects pharmaceuticals and pharmacological or diagnostic tools that target adenosine signaling in their primary or secondary mode of action. We overviewed FDA-approved drugs as well as those currently being studied in clinical trials. Among them are already used in clinic A2A adenosine receptor modulators like istradefylline or regadenoson, but also plenty of anti-platelet, anti-inflammatory, or immunosuppressive, and anti-cancer drugs. On the other hand, we investigated dozens of specific adenosine pathway regulators that are tested in clinical trials to treat human infectious and noninfectious diseases. In conclusion, targeting purinergic signaling represents a great therapeutic challenge. The actual knowledge of the involvement of adenosinergic signaling as part of the mechanism of action of old drugs has open a path not only for drug-repurposing but also for new therapeutic strategies.
Topics: Humans; Adenosine; Adenosine Triphosphate; Receptors, Purinergic P1; Cell Membrane; Signal Transduction
PubMed: 37506580
DOI: 10.1016/j.biopha.2023.115184 -
Circulation Jul 2023The failing heart is traditionally described as metabolically inflexible and oxygen starved, causing energetic deficit and contractile dysfunction. Current metabolic...
BACKGROUND
The failing heart is traditionally described as metabolically inflexible and oxygen starved, causing energetic deficit and contractile dysfunction. Current metabolic modulator therapies aim to increase glucose oxidation to increase oxygen efficiency of adenosine triphosphate production, with mixed results.
METHODS
To investigate metabolic flexibility and oxygen delivery in the failing heart, 20 patients with nonischemic heart failure with reduced ejection fraction (left ventricular ejection fraction 34.9±9.1) underwent separate infusions of insulin+glucose infusion (I+G) or Intralipid infusion. We used cardiovascular magnetic resonance to assess cardiac function and measured energetics using phosphorus-31 magnetic resonance spectroscopy. To investigate the effects of these infusions on cardiac substrate use, function, and myocardial oxygen uptake (MVo), invasive arteriovenous sampling and pressure-volume loops were performed (n=9).
RESULTS
At rest, we found that the heart had considerable metabolic flexibility. During I+G, cardiac glucose uptake and oxidation were predominant (70±14% total energy substrate for adenosine triphosphate production versus 17±16% for Intralipid; =0.002); however, no change in cardiac function was seen relative to basal conditions. In contrast, during Intralipid infusion, cardiac long-chain fatty acid (LCFA) delivery, uptake, LCFA acylcarnitine production, and fatty acid oxidation were all increased (LCFA 73±17% of total substrate versus 19±26% total during I+G; =0.009). Myocardial energetics were better with Intralipid compared with I+G (phosphocreatine/adenosine triphosphate 1.86±0.25 versus 2.01±0.33; =0.02), and systolic and diastolic function were improved (LVEF 34.9±9.1 baseline, 33.7±8.2 I+G, 39.9±9.3 Intralipid; <0.001). During increased cardiac workload, LCFA uptake and oxidation were again increased during both infusions. There was no evidence of systolic dysfunction or lactate efflux at 65% maximal heart rate, suggesting that a metabolic switch to fat did not cause clinically meaningful ischemic metabolism.
CONCLUSIONS
Our findings show that even in nonischemic heart failure with reduced ejection fraction with severely impaired systolic function, significant cardiac metabolic flexibility is retained, including the ability to alter substrate use to match both arterial supply and changes in workload. Increasing LCFA uptake and oxidation is associated with improved myocardial energetics and contractility. Together, these findings challenge aspects of the rationale underlying existing metabolic therapies for heart failure and suggest that strategies promoting fatty acid oxidation may form the basis for future therapies.
Topics: Humans; Stroke Volume; Energy Metabolism; Ventricular Function, Left; Myocardium; Heart Failure; Adenosine Triphosphate; Ventricular Dysfunction, Left; Fatty Acids; Glucose; Oxygen
PubMed: 37199155
DOI: 10.1161/CIRCULATIONAHA.122.062166