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Cold Spring Harbor Perspectives in... May 2021
Review
Topics: Adenosine Triphosphate; Aerobiosis; Animals; Glycolysis; Humans; NAD; Pyruvic Acid; Warburg Effect, Oncologic
PubMed: 33941515
DOI: 10.1101/cshperspect.a040535 -
Nature Jan 2023Inflammasomes are cytosolic innate immune complexes that activate caspase-1 following detection of pathogenic and endogenous dangers, and NACHT-, leucine-rich repeat...
Inflammasomes are cytosolic innate immune complexes that activate caspase-1 following detection of pathogenic and endogenous dangers, and NACHT-, leucine-rich repeat (LRR)- and pyrin domain (PYD)-containing protein 3 (NLRP3) is an inflammasome sensor of membrane damage highly important in regard to the induction of inflammation. Here we report cryogenic electron microscopy structures of disc-shaped active NLRP3 oligomers in complex with adenosine 5'-O-(3-thio)triphosphate, the centrosomal NIMA-related kinase 7 (NEK7) and the adaptor protein ASC, which recruits caspase-1. In these NLRP3-NEK7-ASC complexes, the central NACHT domain of NLRP3 assumes an ATP-bound conformation in which two of its subdomains rotate by about 85° relative to the ADP-bound inactive conformation. The fish-specific NACHT-associated domain conserved in NLRP3 but absent in most NLRPs becomes ordered in its key regions to stabilize the active NACHT conformation and mediate most interactions in the disc. Mutations on these interactions compromise NLRP3-mediated caspase-1 activation. The N-terminal PYDs from all NLRP3 subunits combine to form a PYD filament that recruits ASC PYD to elicit downstream signalling. Surprisingly, the C-terminal LRR domain and the LRR-bound NEK7 do not participate in disc interfaces. Together with previous structures of an inactive NLRP3 cage in which LRR-LRR interactions play an important role, we propose that the role of NEK7 is to break the inactive cage to transform NLRP3 into the active NLRP3 inflammasome disc.
Topics: Animals; Caspase 1; Cryoelectron Microscopy; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Adenosine Triphosphate; Adenosine Diphosphate; CARD Signaling Adaptor Proteins; NIMA-Related Kinases; Protein Domains
PubMed: 36442502
DOI: 10.1038/s41586-022-05570-8 -
Targeting OXPHOS and the electron transport chain in cancer; Molecular and therapeutic implications.Seminars in Cancer Biology Nov 2022Oxidative phosphorylation (OXPHOS) takes place in mitochondria and is the process whereby cells use carbon fuels and oxygen to generate ATP. Formerly OXPHOS was thought... (Review)
Review
Oxidative phosphorylation (OXPHOS) takes place in mitochondria and is the process whereby cells use carbon fuels and oxygen to generate ATP. Formerly OXPHOS was thought to be reduced in tumours and that glycolysis was the critical pathway for generation of ATP but it is now clear that OXPHOS, at least in many tumour types, plays a critical role in delivering the bioenergetic and macromolecular anabolic requirements of cancer cells. There is now great interest in targeting the OXPHOS and the electron transport chain for cancer therapy and in this review article we describe current therapeutic approaches and challenges.
Topics: Humans; Oxidative Phosphorylation; Electron Transport; Glycolysis; Neoplasms; Adenosine Triphosphate
PubMed: 35122973
DOI: 10.1016/j.semcancer.2022.02.002 -
Neuron Mar 2022The purinergic transmitter ATP (adenosine 5'-triphosphate) plays an essential role in both the central and peripheral nervous systems, and the ability to directly...
The purinergic transmitter ATP (adenosine 5'-triphosphate) plays an essential role in both the central and peripheral nervous systems, and the ability to directly measure extracellular ATP in real time will increase our understanding of its physiological functions. Here, we developed a sensitive GPCR activation-based ATP sensor called GRAB, with a robust fluorescence response to extracellular ATP when expressed in several cell types. This sensor has sub-second kinetics, has ATP affinity in the range of tens of nanomolar, and can be used to localize ATP release with subcellular resolution. Using this sensor, we monitored ATP release under a variety of in vitro and in vivo conditions, including stimuli-induced and spontaneous ATP release in primary hippocampal cultures, injury-induced ATP release in a zebrafish model, and lipopolysaccharides-induced ATP-release events in individual astrocytes in the mouse cortex. Thus, the GRAB sensor is a sensitive, versatile tool for monitoring ATP release and dynamics under both physiological and pathophysiological conditions.
Topics: Adenosine Triphosphate; Animals; Astrocytes; Lipopolysaccharides; Mice; Zebrafish
PubMed: 34942116
DOI: 10.1016/j.neuron.2021.11.027 -
Biomolecules Dec 2022Mitochondria calcium is a double-edged sword. While low levels of calcium are essential to maintain optimal rates of ATP production, extreme levels of calcium overcoming... (Review)
Review
Mitochondria calcium is a double-edged sword. While low levels of calcium are essential to maintain optimal rates of ATP production, extreme levels of calcium overcoming the mitochondrial calcium retention capacity leads to loss of mitochondrial function. In moderate amounts, however, ATP synthesis rates are inhibited in a calcium-titratable manner. While the consequences of extreme calcium overload are well-known, the effects on mitochondrial function in the moderately loaded range remain enigmatic. These observations are associated with changes in the mitochondria ultrastructure and cristae network. The present mini review/perspective follows up on previous studies using well-established cryo-electron microscopy and poses an explanation for the observable depressed ATP synthesis rates in mitochondria during calcium-overloaded states. The results presented herein suggest that the inhibition of oxidative phosphorylation is not caused by a direct decoupling of energy metabolism via the opening of a calcium-sensitive, proteinaceous pore but rather a separate but related calcium-dependent phenomenon. Such inhibition during calcium-overloaded states points towards mitochondrial ultrastructural modifications, enzyme activity changes, or an interplay between both events.
Topics: Calcium; Cryoelectron Microscopy; Mitochondria; Energy Metabolism; Adenosine Triphosphate
PubMed: 36551319
DOI: 10.3390/biom12121891 -
The EMBO Journal Jul 2021While intracellular adenosine triphosphate (ATP) occupies a key position in the bioenergetic metabolism of all the cellular compartments that form the tumor... (Review)
Review
While intracellular adenosine triphosphate (ATP) occupies a key position in the bioenergetic metabolism of all the cellular compartments that form the tumor microenvironment (TME), extracellular ATP operates as a potent signal transducer. The net effects of purinergic signaling on the biology of the TME depend not only on the specific receptors and cell types involved, but also on the activation status of cis- and trans-regulatory circuitries. As an additional layer of complexity, extracellular ATP is rapidly catabolized by ectonucleotidases, culminating in the accumulation of metabolites that mediate distinct biological effects. Here, we discuss the molecular and cellular mechanisms through which ATP and its degradation products influence cancer immunosurveillance, with a focus on therapeutically targetable circuitries.
Topics: Adenosine Triphosphate; Animals; Humans; Neoplasms; Signal Transduction; Tumor Microenvironment
PubMed: 34121201
DOI: 10.15252/embj.2021108130 -
Frontiers in Endocrinology 2022Adenosine triphosphate (ATP) serves as the essential source of cellular energy. Over the last two decades, however, ATP has also attracted increasing interest as an... (Review)
Review
Adenosine triphosphate (ATP) serves as the essential source of cellular energy. Over the last two decades, however, ATP has also attracted increasing interest as an extracellular signal that activates purinergic plasma membrane receptors of the P2 family. P2 receptors are divided into two types: ATP-gated nonselective cation channels (P2X) and G protein-coupled receptors (P2Y), the latter being activated by a broad range of purine and pyrimidine nucleotides (ATP, ADP, UTP, and UDP, among others). Purinergic signaling mechanisms are involved in numerous physiological events and pathophysiological conditions. Here, we address the growing body of evidence implicating purinergic signaling in male reproductive system functions. The life-long generation of fertile male germ cells is a highly complex, yet mechanistically poorly understood process. Given the relatively sparse innervation of the testis, spermatogenesis relies on both endocrine control and multi-directional paracrine communication. Therefore, a detailed understanding of such paracrine messengers, including ATP, is crucial to gain mechanistic insight into male reproduction..
Topics: Adenosine Triphosphate; Endocrine System; Humans; Male; Receptors, Purinergic; Signal Transduction; Spermatogenesis
PubMed: 35480481
DOI: 10.3389/fendo.2022.867011 -
Cold Spring Harbor Perspectives in... Mar 2021
Review
Topics: Adenosine Triphosphate; Archaea; Calcium; Citric Acid Cycle; Glucose; Glycolysis; Homeostasis; Mitochondria; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen Consumption; Proteobacteria; Reactive Oxygen Species; Symbiosis
PubMed: 33649187
DOI: 10.1101/cshperspect.a040543 -
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 -
Molecules (Basel, Switzerland) Nov 2020RNA 5'-modifications are known to extend the functional spectrum of ribonucleotides. In recent years, numerous non-canonical 5'-modifications, including...
RNA 5'-modifications are known to extend the functional spectrum of ribonucleotides. In recent years, numerous non-canonical 5'-modifications, including adenosine-containing cofactors from the group of B vitamins, have been confirmed in all kingdoms of life. The structural component of thiamine adenosine triphosphate (thiamine-ATP), a vitamin B1 derivative found to accumulate in and other organisms in response to metabolic stress conditions, suggests an analogous function as a 5'-modification of RNA. Here, we report the synthesis of thiamine adenosine dinucleotides and the preparation of pure 5'-thiamine-capped RNAs based on phosphorimidazolide chemistry. Furthermore, we present the incorporation of thiamine-ATP and thiamine adenosine diphosphate (thiamine-ADP) as 5'-caps of RNA by T7 RNA polymerase. Transcripts containing the thiamine modification were modified specifically with biotin via a combination of thiazole ring opening, nucleophilic substitution and copper-catalyzed azide-alkyne cycloaddition. The highlighted methods provide easy access to 5'-thiamine RNA, which may be applied in the development of thiamine-specific RNA capture protocols as well as the discovery and confirmation of 5'-thiamine-capped RNAs in various organisms.
Topics: Adenosine Triphosphate; Biotinylation; Catalysis; Chemistry Techniques, Synthetic; DNA-Directed RNA Polymerases; Molecular Structure; RNA; RNA Caps; Thiamine; Thiamine Triphosphate; Viral Proteins
PubMed: 33255222
DOI: 10.3390/molecules25235492