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International Journal of Molecular... Oct 2023Fatty acid metabolism, including β-oxidation (βOX), plays an important role in human physiology and pathology. βOX is an essential process in the energy metabolism of... (Review)
Review
Fatty acid metabolism, including β-oxidation (βOX), plays an important role in human physiology and pathology. βOX is an essential process in the energy metabolism of most human cells. Moreover, βOX is also the source of acetyl-CoA, the substrate for (a) ketone bodies synthesis, (b) cholesterol synthesis, (c) phase II detoxication, (d) protein acetylation, and (d) the synthesis of many other compounds, including N-acetylglutamate-an important regulator of urea synthesis. This review describes the current knowledge on the importance of the mitochondrial and peroxisomal βOX in various organs, including the liver, heart, kidney, lung, gastrointestinal tract, peripheral white blood cells, and other cells. In addition, the diseases associated with a disturbance of fatty acid oxidation (FAO) in the liver, heart, kidney, lung, alimentary tract, and other organs or cells are presented. Special attention was paid to abnormalities of FAO in cancer cells and the diseases caused by mutations in gene-encoding enzymes involved in FAO. Finally, issues related to α- and ω- fatty acid oxidation are discussed.
Topics: Humans; Acyl Coenzyme A; Fatty Acids; Oxidation-Reduction; Liver; Acetyl Coenzyme A
PubMed: 37834305
DOI: 10.3390/ijms241914857 -
International Journal of Molecular... Jun 2024Tumor cells reprogram their metabolism to meet the increased demand for nucleotides and other molecules necessary for growth and proliferation. In fact, cancer cells are... (Review)
Review
Tumor cells reprogram their metabolism to meet the increased demand for nucleotides and other molecules necessary for growth and proliferation. In fact, cancer cells are characterized by an increased "de novo" synthesis of purine nucleotides. Therefore, it is not surprising that specific enzymes of purine metabolism are the targets of drugs as antineoplastic agents, and a better knowledge of the mechanisms underlying their regulation would be of great help in finding new therapeutic approaches. The mammalian target of the rapamycin (mTOR) signaling pathway, which is often activated in cancer cells, promotes anabolic processes and is a major regulator of cell growth and division. Among the numerous effects exerted by mTOR, noteworthy is its empowerment of the "de novo" synthesis of nucleotides, accomplished by supporting the formation of purinosomes, and by increasing the availability of necessary precursors, such as one-carbon formyl group, bicarbonate and 5-phosphoribosyl-1-pyrophosphate. In this review, we highlight the connection between purine and mitochondrial metabolism, and the bidirectional relation between mTOR signaling and purine synthesis pathways.
Topics: Humans; Neoplasms; TOR Serine-Threonine Kinases; Purines; Signal Transduction; Animals; Mitochondria
PubMed: 38928439
DOI: 10.3390/ijms25126735 -
Nature Communications Aug 2023Purine-containing nucleotide second messengers regulate diverse cellular activities. Cyclic di-pyrimidines mediate anti-phage functions in bacteria; however, the...
Purine-containing nucleotide second messengers regulate diverse cellular activities. Cyclic di-pyrimidines mediate anti-phage functions in bacteria; however, the synthesis mechanism remains elusive. Here, we determine the high-resolution structures of cyclic di-pyrimidine-synthesizing cGAS/DncV-like nucleotidyltransferases (CD-NTases) in clade E (CdnE) in its apo, substrate-, and intermediate-bound states. A conserved (R/Q)xW motif controlling the pyrimidine specificity of donor nucleotide is identified. Mutation of Trp or Arg from the (R/Q)xW motif to Ala rewires its specificity to purine nucleotides, producing mixed purine-pyrimidine cyclic dinucleotides (CDNs). Preferential binding of uracil over cytosine bases explains the product specificity of cyclic di-pyrimidine-synthesizing CdnE to cyclic di-UMP (cUU). Based on the intermediate-bound structures, a synthetic pathway for cUU containing a unique 2'3'-phosphodiester linkage through intermediate pppU[3'-5']pU is deduced. Our results provide a framework for pyrimidine selection and establish the importance of conserved residues at the C-terminal loop for the specificity determination of CD-NTases.
Topics: Pyrimidines; Nucleotidyltransferases; Nucleotides; Chromogranin A; Purine Nucleotides
PubMed: 37604815
DOI: 10.1038/s41467-023-40787-9 -
Molecular Biology Reports Sep 2023Anxiety and depression disorders are highly prevalent neurological disorders (NDs) that impact up to one in three individuals during their lifetime. Addressing these... (Review)
Review
Anxiety and depression disorders are highly prevalent neurological disorders (NDs) that impact up to one in three individuals during their lifetime. Addressing these disorders requires reducing their frequency and impact, understanding molecular causes, implementing prevention strategies, and improving treatments. Cyclic nucleotide monophosphates (cNMPs) like cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), cyclic uridine monophosphate (cUMP), and cyclic cytidine monophosphate (cCMP) regulate the transcription of genes involved in neurotransmitters and neurological functions. Evidence suggests that cNMP pathways, including cAMP/cGMP, cAMP response element binding protein (CREB), and Protein kinase A (PKA), play a role in the physiopathology of anxiety and depression disorders. Plant and mushroom-based compounds have been used in traditional and modern medicine due to their beneficial properties. Bioactive compound metabolism can activate key pathways and yield pharmacological outcomes. This review focuses on the molecular mechanisms of bioactive compounds from plants and mushrooms in modulating cNMP pathways. Understanding these processes will support current treatments and aid in the development of novel approaches to reduce the prevalence of anxiety and depression disorders, contributing to improved outcomes and the prevention of associated complications.
Topics: Humans; Nucleotides, Cyclic; Depression; Cyclic GMP; Cyclic AMP; Plants; Anxiety
PubMed: 37486442
DOI: 10.1007/s11033-023-08650-8 -
Communications Biology Aug 2023Renal ischemia/reperfusion (I/R) injury contributes to the development of acute kidney injury (AKI). Kidney is the second organ rich in mitochondrial content next to the...
Renal ischemia/reperfusion (I/R) injury contributes to the development of acute kidney injury (AKI). Kidney is the second organ rich in mitochondrial content next to the heart. Mitochondrial damage substantially contributes for AKI development. Mitophagy eliminates damaged mitochondria from the cells to maintain a healthy mitochondrial population, which plays an important role in AKI. Pannexin 1 (PANX1) channel transmembrane proteins are known to drive inflammation and release of adenosine triphosphate (ATP) during I/R injury. However, the specific role of PANX1 on mitophagy regulation in renal I/R injury remains elusive. In this study, we find that serum level of PANX1 is elevated in patients who developed AKI after cardiac surgery, and the level of PANX1 is positively correlated with serum creatinine and urea nitrogen levels. Using the mouse model of renal I/R injury in vivo and cell-based hypoxia/reoxygenation (H/R) model in vitro, we prove that genetic deletion of PANX1 mitigate the kidney tubular cell death, oxidative stress and mitochondrial damage after I/R injury through enhanced mitophagy. Mechanistically, PANX1 disrupts mitophagy by influencing ATP-P2Y-mTOR signal pathway. These observations provide evidence that PANX1 could be a potential biomarker for AKI and a therapeutic target to alleviate AKI caused by I/R injury.
Topics: Animals; Mice; Mitophagy; Kidney; Acute Kidney Injury; Adenosine Triphosphate; Ischemia
PubMed: 37644178
DOI: 10.1038/s42003-023-05226-x -
Physiological Reviews Apr 2024Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine... (Review)
Review
Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both cyclic nucleotides are critical secondary messengers in the neurohormonal regulation in the cardiovascular system. PDEs precisely control spatiotemporal subcellular distribution of cyclic nucleotides in a cell- and tissue-specific manner, playing critical roles in physiological responses to hormone stimulation in the heart and vessels. Dysregulation of PDEs has been linked to the development of several cardiovascular diseases, such as hypertension, aneurysm, atherosclerosis, arrhythmia, and heart failure. Targeting these enzymes has been proven effective in treating cardiovascular diseases and is an attractive and promising strategy for the development of new drugs. In this review, we discuss the current understanding of the complex regulation of PDE isoforms in cardiovascular function, highlighting the divergent and even opposing roles of PDE isoforms in different pathogenesis.
Topics: Humans; Phosphoric Diester Hydrolases; Cardiovascular Diseases; Phosphodiesterase Inhibitors; Cyclic AMP; Cyclic GMP; Protein Isoforms; Diethylstilbestrol
PubMed: 37971403
DOI: 10.1152/physrev.00015.2023 -
Aging and Disease Apr 2024Nicotinamide adenine dinucleotide (NAD) has recently attracted much attention due to its role in aging and lifespan extension. NAD directly and indirectly affects many... (Review)
Review
Nicotinamide adenine dinucleotide (NAD) has recently attracted much attention due to its role in aging and lifespan extension. NAD directly and indirectly affects many cellular processes, including metabolic pathways, DNA repair, and immune cell activities. These mechanisms are critical for maintaining cellular homeostasis. However, the decline in NAD levels with aging impairs tissue function, which has been associated with several age-related diseases. In fact, the aging population has been steadily increasing worldwide, and it is important to restore NAD levels and reverse or delay these age-related disorders. Therefore, there is an increasing demand for healthy products that can mitigate aging, extend lifespan, and halt age-related consequences. In this case, several studies in humans and animals have targeted NAD metabolism with NAD intermediates. Among them, nicotinamide mononucleotide (NMN), a precursor in the biosynthesis of NAD, has recently received much attention from the scientific community for its anti-aging properties. In model organisms, ingestion of NMN has been shown to improve age-related diseases and probably delay death. Here, we review aspects of NMN biosynthesis and the mechanism of its absorption, as well as potential anti-aging mechanisms of NMN, including recent preclinical and clinical tests, adverse effects, limitations, and perceived challenges.
Topics: Humans; Animals; Aged; NAD; Nicotinamide Mononucleotide; Aging; Longevity; Homeostasis
PubMed: 37548938
DOI: 10.14336/AD.2023.0519-1 -
Cell Communication and Signaling : CCS Sep 2023Cyclic bis-(3', 5')-dimeric guanosine monophosphate (c-di-GMP) is ubiquitous in many bacterial species, where it functions as a nucleotide-based secondary messenger and... (Review)
Review
Cyclic bis-(3', 5')-dimeric guanosine monophosphate (c-di-GMP) is ubiquitous in many bacterial species, where it functions as a nucleotide-based secondary messenger and is a vital regulator of numerous biological processes. Due to its ubiquity, most bacterial species possess a wide range of downstream receptors that has a binding affinity to c-di-GMP and elicit output responses. In eukaryotes, several enzymes and riboswitches operate as receptors that interact with c-di-GMP and transduce cellular or environmental signals. This review examines the functional variety of receptors in prokaryotic and eukaryotic systems that exhibit distinct biological responses after interacting with c-di-GMP. Evolutionary relationships and similarities in distance among the c-di-GMP receptors in various bacterial species were evaluated to understand their specificities. Furthermore, residues of receptors involved in c-di-GMP binding are summarized. This review facilitates the understanding of how distinct receptors from different origins bind c-di-GMP equally well, yet fulfill diverse biological roles at the interspecies, intraspecies, and interkingdom levels. Furthermore, it also highlights c-di-GMP receptors as potential therapeutic targets, particularly those found in pathogenic microorganisms. Video Abstract.
Topics: Eukaryota; Cyclic GMP; Phosphorylation; Polymers
PubMed: 37749602
DOI: 10.1186/s12964-023-01263-5 -
Cell Communication and Signaling : CCS Aug 2023Mesenchymal stem cells (MSCs) have emerged as a promising alternative treatment for liver disease due to their roles in regeneration, fibrosis inhibition, and... (Review)
Review
Mesenchymal stem cells (MSCs) have emerged as a promising alternative treatment for liver disease due to their roles in regeneration, fibrosis inhibition, and immunoregulation. Mitochondria are crucial in maintaining hepatocyte integrity and function. Mitochondrial dysfunction, such as impaired synthesis of adenosine triphosphate (ATP), decreased activity of respiratory chain complexes, and altered mitochondrial dynamics, is observed in most liver diseases. Accumulating evidence has substantiated that the therapeutic potential of MSCs is mediated not only through their cell replacement and paracrine effects but also through their regulation of mitochondrial dysfunction in liver disease. Here, we comprehensively review the involvement of mitochondrial dysfunction in the development of liver disease and how MSCs can target mitochondrial dysfunction. We also discuss recent advances in a novel method that modifies MSCs to enhance their functions in liver disease. A full understanding of MSC restoration of mitochondrial function and the underlying mechanisms will provide innovative strategies for clinical applications. Video Abstract.
Topics: Humans; Liver Diseases; Mitochondria; Mitochondrial Membranes; Adenosine Triphosphate; Mesenchymal Stem Cells
PubMed: 37596671
DOI: 10.1186/s12964-023-01230-0 -
ELife Oct 2023Accumulating evidence indicates that acetate is increased under energy stress conditions such as those that occur in diabetes mellitus and prolonged starvation. However,...
Accumulating evidence indicates that acetate is increased under energy stress conditions such as those that occur in diabetes mellitus and prolonged starvation. However, how and where acetate is produced and the nature of its biological significance are largely unknown. We observed overproduction of acetate to concentrations comparable to those of ketone bodies in patients and mice with diabetes or starvation. Mechanistically, ACOT12 and ACOT8 are dramatically upregulated in the liver to convert free fatty acid-derived acetyl-CoA to acetate and CoA. This conversion not only provides a large amount of acetate, which preferentially fuels the brain rather than muscle, but also recycles CoA, which is required for sustained fatty acid oxidation and ketogenesis. We suggest that acetate is an emerging novel 'ketone body' that may be used as a parameter to evaluate the progression of energy stress.
Topics: Humans; Animals; Mice; Acetyl Coenzyme A; Liver; Acetates; Brain; Fatty Acids, Nonesterified; Ketone Bodies; Starvation; Thiolester Hydrolases
PubMed: 37902629
DOI: 10.7554/eLife.87419