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CoA in Health and Disease 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 16834

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Dr. Pawel Dobrzyn

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Laboratory of Molecular Medical Biochemistry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland
Interests: physiology; endocrinology; metabolism; lipids; lipogenesis; lipolysis; stearoyl-CoA desaturase; angiogenesis; cardiovascular system; mitochondria; obesity; type 2 diabetes; transcription factors
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Special Issue Information

Dear Colleagues,

CoA and its thioester derivatives are crucial components of numerous biosynthetic and degradative pathways of cellular metabolism (including the synthesis and oxidation of fatty acids, the Krebs cycle, ketogenesis, the biosynthesis of cholesterol and acetylcholine, and the degradation of amino acids), post-translational modifications of proteins, and the regulation of gene expression. Consequently, it is not surprising that the abnormal biosynthesis of CoA/CoA derivatives is associated with numerous pathologies, including diabetes, neurodegeneration, Reye’s syndrome, vitamin B12 deficiency, cardiac hypertrophy, and cancer. This Special Issue of IJMS will showcase selected novel research articles covering the multiple roles of CoA and its derivatives in extracellular and intracellular signaling functions in physiology and pathology.

Topics of interest to this Special Issue include, but are not limited to, the following:

CoA synthesis and degradation;
CoA transport and mitochondria;
Extracellular functions of CoA/CoA thioesters;
CoA/CoA thioesters as intracellular signaling molecules;
Physiological and pathological changes in cellular CoA concentrations;
Interconversion between CoA and its thioester derivatives in health and disease;
The role of nutrients, hormones, and other factors in the regulation of CoA levels in cells;
Acyl-CoA metabolism;
Association of CoA/acyl-CoA with fatty acid metabolism.

In addition, critical reviews of the status and perspectives regarding the role of CoA in pathophysiology are welcomed.

Dr. Pawel Dobrzyn
Guest Editor

Manuscript Submission Information

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Keywords

energy production
impaired metabolism
Acyl-CoA synthesis and function
Acetyl-CoA
CoA analogues
oxidative stress
hereditary diseases

Published Papers (9 papers)

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15 pages, 2417 KiB

Open AccessArticle

Changes of the Protein CoAlation Pattern in Response to Oxidative Stress and Capacitation in Human Spermatozoa

by Olivia Petrone, Steven Serafini, Bess Yi Kun Yu, Valeriy Filonenko, Ivan Gout and Cristian O’Flaherty

Int. J. Mol. Sci. 2023, 24(15), 12526; https://doi.org/10.3390/ijms241512526 - 07 Aug 2023

Cited by 1 | Viewed by 1201

Abstract

The spermatozoa have limited antioxidant defences, a high polyunsaturated fatty acids content and the impossibility of synthesizing proteins, thus being susceptible to oxidative stress. High levels of reactive oxygen species (ROS) harm human spermatozoa, promoting oxidative damage to sperm lipids, proteins and DNA, leading to infertility. Coenzyme A (CoA) is a key metabolic integrator in all living cells. Recently, CoA was shown to function as a major cellular antioxidant mediated by a covalent modification of surface-exposed cysteines by CoA (protein CoAlation) under oxidative or metabolic stresses. Here, the profile of protein CoAlation was examined in sperm capacitation and in human spermatozoa treated with different oxidizing agents (hydrogen peroxide, (H₂O₂), diamide and tert-butyl hydroperoxide (t-BHP). Sperm viability and motility were also investigated. We found that H₂O₂ and diamide produced the highest levels of protein CoAlation and the greatest reduction of sperm motility without impairing viability. Protein CoAlation levels are regulated by 2-Cys peroxiredoxins (PRDXs). Capacitated spermatozoa showed lower levels of protein CoAlation than non-capacitation cells. This study is the first to demonstrate that PRDXs regulate protein CoAlation, which is part of the antioxidant response of human spermatozoa and participates in the redox regulation associated with sperm capacitation. Full article

(This article belongs to the Special Issue CoA in Health and Disease 2.0)

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17 pages, 3565 KiB

Open AccessArticle

A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1

by Maria-Armineh Tossounian, Stefan Denchev Hristov, Jonathan Alexis Semelak, Bess Yi Kun Yu, Maria Baczynska, Yuhan Zhao, Dario Ariel Estrin, Madia Trujillo, Valeriy Filonenko, Jerome Gouge and Ivan Gout

Int. J. Mol. Sci. 2023, 24(11), 9359; https://doi.org/10.3390/ijms24119359 - 27 May 2023

Cited by 1 | Viewed by 1870

Abstract

Coenzyme A (CoA) is a key cellular metabolite which participates in diverse metabolic pathways, regulation of gene expression and the antioxidant defense mechanism. Human NME1 (hNME1), which is a moonlighting protein, was identified as a major CoA-binding protein. Biochemical studies showed that hNME1 is regulated by CoA through both covalent and non-covalent binding, which leads to a decrease in the hNME1 nucleoside diphosphate kinase (NDPK) activity. In this study, we expanded the knowledge on previous findings by focusing on the non-covalent mode of CoA binding to the hNME1. With X-ray crystallography, we solved the CoA bound structure of hNME1 (hNME1-CoA) and determined the stabilization interactions CoA forms within the nucleotide-binding site of hNME1. A hydrophobic patch stabilizing the CoA adenine ring, while salt bridges and hydrogen bonds stabilizing the phosphate groups of CoA were observed. With molecular dynamics studies, we extended our structural analysis by characterizing the hNME1-CoA structure and elucidating possible orientations of the pantetheine tail, which is absent in the X-ray structure due to its flexibility. Crystallographic studies suggested the involvement of arginine 58 and threonine 94 in mediating specific interactions with CoA. Site-directed mutagenesis and CoA-based affinity purifications showed that arginine 58 mutation to glutamate (R58E) and threonine 94 mutation to aspartate (T94D) prevent hNME1 from binding to CoA. Overall, our results reveal a unique mode by which hNME1 binds CoA, which differs significantly from that of ADP binding: the α- and β-phosphates of CoA are oriented away from the nucleotide-binding site, while 3′-phosphate faces catalytic histidine 118 (H118). The interactions formed by the CoA adenine ring and phosphate groups contribute to the specific mode of CoA binding to hNME1. Full article

(This article belongs to the Special Issue CoA in Health and Disease 2.0)

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18 pages, 3342 KiB

Open AccessArticle

Molecular Basis of Unequal Alternative Splicing of Human SCD5 and Its Alteration by Natural Genetic Variations

by Gabriella Orosz, Luca Szabó, Szanna Bereti, Veronika Zámbó, Miklós Csala and Éva Kereszturi

Int. J. Mol. Sci. 2023, 24(7), 6517; https://doi.org/10.3390/ijms24076517 - 30 Mar 2023

Viewed by 1330

Abstract

Alternative splicing (AS) is a major means of post-transcriptional control of gene expression, and provides a dynamic versatility of protein isoforms. Cancer-related AS disorders have diagnostic, prognostic and therapeutic values. Changes in the expression and AS of human stearoyl-CoA desaturase-5 (SCD5) are promising specific tumor markers, although the transcript variants (TVs) of the gene have not yet been confirmed. Our in silico, in vitro and in vivo study focuses on the distribution of SCD5 TVs (A and B) in human tissues, the functionality of the relevant splice sites, and their modulation by certain single-nucleotide variations (SNVs). An order of magnitude higher SCD5A expression was found compared with SCD5B. This unequal splicing is attributed to a weaker recognition of the SCD5B-specific splicing acceptor site, based on predictions confirmed by an optimized minigene assay. The pronounced dominance of SCD5A was largely modified (rs1430176385_A, rs1011850309_A) or even inverted (rs1011850309_C) by natural SNVs at the TV-specific splice sites. Our results provide long missing data on the proportion of SCD5 TVs in human tissues and reveal mutation-driven changes in SCD5 AS, potentially affecting tumor-associated reprogramming of lipid metabolism, thus having prognostic significance, which may be utilized for novel and personalized therapeutic approaches. Full article

(This article belongs to the Special Issue CoA in Health and Disease 2.0)

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13 pages, 748 KiB

Open AccessArticle

Rats with Long-Term Cholestasis Have a Decreased Cytosolic but Maintained Mitochondrial Hepatic CoA Pool

by Lukas Krähenbühl and Stephan Krähenbühl

Int. J. Mol. Sci. 2023, 24(5), 4365; https://doi.org/10.3390/ijms24054365 - 22 Feb 2023

Viewed by 958

Abstract

Previous studies showed that rats with long-term bile duct ligation have reduced coenzyme A stores per g of liver but maintained mitochondrial CoA stores. Based on these observations, we determined the CoA pool in the liver homogenate, liver mitochondria, and liver cytosol of rats with bile duct ligation for 4 weeks (BDL rats, n = 9) and sham-operated control rats (CON rats, n = 5). In addition, we tested the cytosolic and mitochondrial CoA pools by assessing the metabolism of sulfamethoxazole and benzoate in vivo and of palmitate in vitro. The hepatic total CoA content was lower in BDL than CON rats (mean ± SEM; 128 ± 5 vs. 210 ± 9 nmol/g), affecting all subfractions equally (free CoA (CoASH), short- and long-chain acyl-CoA). In BDL rats, the hepatic mitochondrial CoA pool was maintained, and the cytosolic pool was reduced (23.0 ± 0.9 vs. 84.6 ± 3.7 nmol/g liver; CoA subfractions were affected equally). The urinary excretion of hippurate after i.p. benzoate administration (measuring mitochondrial benzoate activation) was reduced in BDL rats (23.0 ± 0.9 vs. 48.6 ± 3.7% of dose/24 h), whereas the urinary elimination of N-acetylsulfamethoxazole after i.p. sulfamethoxazole administration (measuring the cytosolic acetyl-CoA pool) was maintained (36.6 ± 3.0 vs. 35.1 ± 2.5% of dose/24 h BDL vs. CON rats). Palmitate activation was impaired in the liver homogenate of BDL rats but the cytosolic CoASH concentration was not limiting. In conclusion, BDL rats have reduced hepatocellular cytosolic CoA stores, but this reduction does not limit sulfamethoxazole N-acetylation or palmitate activation. The hepatocellular mitochondrial CoA pool is maintained in BDL rats. Impaired hippurate formation in BDL rats is explained best by mitochondrial dysfunction. Full article

(This article belongs to the Special Issue CoA in Health and Disease 2.0)

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19 pages, 14249 KiB

Open AccessArticle

Stearoyl-CoA Desaturase Regulates Angiogenesis and Energy Metabolism in Ischemic Cardiomyocytes

by Ana-Maria Gan, Zuzanna Tracz-Gaszewska, Aleksandra Ellert-Miklaszewska, Viktor O. Navrulin, James M. Ntambi and Pawel Dobrzyn

Int. J. Mol. Sci. 2022, 23(18), 10459; https://doi.org/10.3390/ijms231810459 - 09 Sep 2022

Cited by 5 | Viewed by 2007

Abstract

New blood vessel formation is a key component of the cardiac repair process after myocardial infarction (MI). Hypoxia following MI is a major driver of angiogenesis in the myocardium. Hypoxia-inducible factor 1α (HIF1α) is the key regulator of proangiogenic signaling. The present study found that stearoyl-CoA desaturase (SCD) significantly contributed to the induction of angiogenesis in the hypoxic myocardium independently of HIF1α expression. The pharmacological inhibition of SCD activity in HL-1 cardiomyocytes and SCD knockout in an animal model disturbed the expression and secretion of proangiogenic factors including vascular endothelial growth factor-A, proinflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor α, monocyte chemoattractant protein-1, and Rantes), metalloproteinase-9, and platelet-derived growth factor in ischemic cardiomyocytes. These disturbances affected the proangiogenic potential of ischemic cardiomyocytes after SCD depletion. Together with the most abundant SCD1 isoform, the heart-specific SCD4 isoform emerged as an important regulator of new blood vessel formation in the murine post-MI myocardium. We also provide evidence that SCD shapes energy metabolism of the ischemic heart by maintaining the shift from fatty acids to glucose as the substrate that is used for adenosine triphosphate production. Furthermore, we propose that the regulation of the proangiogenic properties of hypoxic cardiomyocytes by key modulators of metabolic signaling such as adenosine monophosphate kinase, protein kinase B (AKT), and peroxisome-proliferator-activated receptor-γ coactivator 1α/peroxisome proliferator-activated receptor α depends on SCD to some extent. Thus, our results reveal a novel mechanism that links SCD to cardiac repair processes after MI. Full article

(This article belongs to the Special Issue CoA in Health and Disease 2.0)

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Review

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50 pages, 2557 KiB

Open AccessReview

The Physiological and Pathological Role of Acyl-CoA Oxidation

by Sylwia Szrok-Jurga, Aleksandra Czumaj, Jacek Turyn, Areta Hebanowska, Julian Swierczynski, Tomasz Sledzinski and Ewa Stelmanska

Int. J. Mol. Sci. 2023, 24(19), 14857; https://doi.org/10.3390/ijms241914857 - 03 Oct 2023

Viewed by 3426

Abstract

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. Full article

(This article belongs to the Special Issue CoA in Health and Disease 2.0)

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18 pages, 1535 KiB

Open AccessReview

Starving the Beast: Limiting Coenzyme A Biosynthesis to Prevent Disease and Transmission in Malaria

by Brendan F. Riske, Shirley Luckhart and Michael A. Riehle

Int. J. Mol. Sci. 2023, 24(18), 13915; https://doi.org/10.3390/ijms241813915 - 10 Sep 2023

Viewed by 1063

Abstract

Malaria parasites must acquire all necessary nutrients from the vertebrate and mosquito hosts to successfully complete their life cycle. Failure to acquire these nutrients can limit or even block parasite development and presents a novel target for malaria control. One such essential nutrient is pantothenate, also known as vitamin B5, which the parasite cannot synthesize de novo and is required for the synthesis of coenzyme A (CoA) in the parasite. This review examines pantothenate and the CoA biosynthesis pathway in the human–mosquito–malaria parasite triad and explores possible approaches to leverage the CoA biosynthesis pathway to limit malaria parasite development in both human and mosquito hosts. This includes a discussion of sources for pantothenate for the mosquito, human, and parasite, examining the diverse strategies used by the parasite to acquire substrates for CoA synthesis across life stages and host resource pools and a discussion of drugs and alternative approaches being studied to disrupt CoA biosynthesis in the parasite. The latter includes antimalarial pantothenate analogs, known as pantothenamides, that have been developed to target this pathway during the human erythrocytic stages. In addition to these parasite-targeted drugs, we review studies of mosquito-targeted allosteric enzymatic regulators known as pantazines as an approach to limit pantothenate availability in the mosquito and subsequently deprive the parasite of this essential nutrient. Full article

(This article belongs to the Special Issue CoA in Health and Disease 2.0)

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22 pages, 1779 KiB

Open AccessReview

Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

by Chiara Cavestro, Daria Diodato, Valeria Tiranti and Ivano Di Meo

Int. J. Mol. Sci. 2023, 24(6), 5951; https://doi.org/10.3390/ijms24065951 - 21 Mar 2023

Cited by 3 | Viewed by 2229

Abstract

Coenzyme A (CoA) is a vital and ubiquitous cofactor required in a vast number of enzymatic reactions and cellular processes. To date, four rare human inborn errors of CoA biosynthesis have been described. These disorders have distinct symptoms, although all stem from variants in genes that encode enzymes involved in the same metabolic process. The first and last enzymes catalyzing the CoA biosynthetic pathway are associated with two neurological conditions, namely pantothenate kinase-associated neurodegeneration (PKAN) and COASY protein-associated neurodegeneration (CoPAN), which belong to the heterogeneous group of neurodegenerations with brain iron accumulation (NBIA), while the second and third enzymes are linked to a rapidly fatal dilated cardiomyopathy. There is still limited information about the pathogenesis of these diseases, and the knowledge gaps need to be resolved in order to develop potential therapeutic approaches. This review aims to provide a summary of CoA metabolism and functions, and a comprehensive overview of what is currently known about disorders associated with its biosynthesis, including available preclinical models, proposed pathomechanisms, and potential therapeutic approaches. Full article

(This article belongs to the Special Issue CoA in Health and Disease 2.0)

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15 pages, 933 KiB

Open AccessReview

Role of Stearoyl-CoA Desaturase 1 in Cardiovascular Physiology

by Volodymyr V. Balatskyi and Pawel Dobrzyn

Int. J. Mol. Sci. 2023, 24(6), 5531; https://doi.org/10.3390/ijms24065531 - 14 Mar 2023

Cited by 5 | Viewed by 2112

Abstract

Stearoyl-CoA desaturase is a rate-limiting enzyme in the synthesis of monounsaturated fatty acids. Monounsaturated fatty acids limit the toxicity of exogenous saturated fats. Studies have shown that stearoyl-CoA desaturase 1 is involved in the remodeling of cardiac metabolism. The loss of stearoyl-CoA desaturase 1 reduces fatty acid oxidation and increases glucose oxidation in the heart. Such a change is protective under conditions of a high-fat diet, which reduces reactive oxygen species-generating β-oxidation. In contrast, stearoyl-CoA desaturase 1 deficiency predisposes individuals to atherosclerosis under conditions of hyperlipidemia but protects against apnea-induced atherosclerosis. Stearoyl-CoA desaturase 1 deficiency also impairs angiogenesis after myocardial infarction. Clinical data show a positive correlation between blood stearoyl-CoA Δ-9 desaturation rates and cardiovascular disease and mortality. Moreover, stearoyl-CoA desaturase inhibition is considered an attractive intervention in some obesity-associated pathologies, and the importance of stearoyl-CoA desaturase in the cardiovascular system might be a limitation for developing such therapy. This review discusses the role of stearoyl-CoA desaturase 1 in the regulation of cardiovascular homeostasis and the development of heart disease and presents markers of systemic stearoyl-CoA desaturase activity and their predictive potential in the diagnosis of cardiovascular disorders. Full article

(This article belongs to the Special Issue CoA in Health and Disease 2.0)

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