The Pathophysiological Role of CoA

Czumaj, Aleksandra; Szrok-Jurga, Sylwia; Hebanowska, Areta; Turyn, Jacek; Świerczyński, Julian; Śledziński, Tomasz; Stelmańska, Ewa

doi:10.3390/ijms21239057

Cited by 76 publications

(65 citation statements)

References 187 publications

(253 reference statements)

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“…It is important to determine if the lifespan extension mediated by pantothenate supplementation is mediated by increased hypothalamic acetyl-CoA levels and histone acetylation. CoA-SH metabolism and its role in disease were recently reviewed [ 282 ].…”

Section: Pyruvate Ketone Bodies Citric Acid Cycle Metabolites or Pantothenate Supplementation May Increase Nucleocytoplasmic Acetyl-coa Lmentioning

confidence: 99%

Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

Bradshaw

2021

Antioxidants

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Acetyl-CoA is a metabolite at the crossroads of central metabolism and the substrate of histone acetyltransferases regulating gene expression. In many tissues fasting or lifespan extending calorie restriction (CR) decreases glucose-derived metabolic flux through ATP-citrate lyase (ACLY) to reduce cytoplasmic acetyl-CoA levels to decrease activity of the p300 histone acetyltransferase (HAT) stimulating pro-longevity autophagy. Because of this, compounds that decrease cytoplasmic acetyl-CoA have been described as CR mimetics. But few authors have highlighted the potential longevity promoting roles of nuclear acetyl-CoA. For example, increasing nuclear acetyl-CoA levels increases histone acetylation and administration of class I histone deacetylase (HDAC) inhibitors increases longevity through increased histone acetylation. Therefore, increased nuclear acetyl-CoA likely plays an important role in promoting longevity. Although cytoplasmic acetyl-CoA synthetase 2 (ACSS2) promotes aging by decreasing autophagy in some peripheral tissues, increased glial AMPK activity or neuronal differentiation can stimulate ACSS2 nuclear translocation and chromatin association. ACSS2 nuclear translocation can result in increased activity of CREB binding protein (CBP), p300/CBP-associated factor (PCAF), and other HATs to increase histone acetylation on the promoter of neuroprotective genes including transcription factor EB (TFEB) target genes resulting in increased lysosomal biogenesis and autophagy. Much of what is known regarding acetyl-CoA metabolism and aging has come from pioneering studies with yeast, fruit flies, and nematodes. These studies have identified evolutionary conserved roles for histone acetylation in promoting longevity. Future studies should focus on the role of nuclear acetyl-CoA and histone acetylation in the control of hypothalamic inflammation, an important driver of organismal aging.

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Section: Pyruvate Ketone Bodies Citric Acid Cycle Metabolites or Pantothenate Supplementation May Increase Nucleocytoplasmic Acetyl-coa Lmentioning

confidence: 99%

Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

Bradshaw

2021

Antioxidants

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“…The synthesis of CoA is thought to take place in the cytosol, where most of the enzymes are found [14]. Recent data show that both PANK and COASY enzymes may have other localization in some eukaryotic cells, thus raising the possibility of compartmentalized biosynthetic processes [15]. In humans, there are 4 active PANK isoforms: PANK1a and PANK1b derive from the same gene with an alternative starting exon.…”

Section: De Novo Coa Biosynthesismentioning

confidence: 99%

“…Acyl groups transferred by the carnitine shuttle and CoA are essential substrates for mitochondrial beta-oxidation and this type of regulation connects PANK2 activity with the status of this essential catabolic pathway. In addition, the final step in CoA production represents another point of regulation of the pathway, particularly when the flux through the pathway is increased; CoA and CoA thioesters exert a feedback inhibitory control on mammalian COASY activity [15].…”

Section: De Novo Coa Biosynthesismentioning

confidence: 99%

“…Given the large diffusion of Pan in nature, disorders due to reduced CoA concentrations are not common and generally related to defects in the biochemical processes controlling its homeostasis, including the biosynthesis, degradation and distribution [15,52]. There are data indicating a relevant connection between improper intracellular CoA handling and myopathies: mutations in the PPCS gene, coding for the enzyme catalyzing the second step in CoA biosynthesis (Figure 1), cause an autosomal recessive dilated cardiomyopathy [53], whereas defects in SLC25A42, the mitochondrial transporters of CoA, leads to variable clinical phenotype with myopathy [54,55].…”

Section: Coa Biosynthesis and Neurodegenerationmentioning

confidence: 99%

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Coenzyme a Biochemistry: From Neurodevelopment to Neurodegeneration

et al. 2021

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Coenzyme A (CoA) is an essential cofactor in all living organisms. It is involved in a large number of biochemical processes functioning either as an activator of molecules with carbonyl groups or as a carrier of acyl moieties. Together with its thioester derivatives, it plays a central role in cell metabolism, post-translational modification, and gene expression. Furthermore, recent studies revealed a role for CoA in the redox regulation by the S-thiolation of cysteine residues in cellular proteins. The intracellular concentration and distribution in different cellular compartments of CoA and its derivatives are controlled by several extracellular stimuli such as nutrients, hormones, metabolites, and cellular stresses. Perturbations of the biosynthesis and homeostasis of CoA and/or acyl-CoA are connected with several pathological conditions, including cancer, myopathies, and cardiomyopathies. In the most recent years, defects in genes involved in CoA production and distribution have been found in patients affected by rare forms of neurodegenerative and neurodevelopmental disorders. In this review, we will summarize the most relevant aspects of CoA cellular metabolism, their role in the pathogenesis of selected neurodevelopmental and neurodegenerative disorders, and recent advancements in the search for therapeutic approaches for such diseases.

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“…Coenzyme A (CoA) has a clearly defined role as a cofactor for a number of oxidative and biosynthetic reactions in intermediary metabolism [ 1 , 2 ]. It is involved in cellular metabolism (fatty acid synthesis, tricarboxylic acid cycle, oxidation of fatty acid, bile acid conjugation), production of neurotransmitters, regulation of gene expression [ 3 ], redox regulation, protein quality control and autophagy [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Turnover rate of coenzyme A in mouse brain and liver

et al. 2021

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Coenzyme A (CoA) is a fundamental cofactor involved in a number of important biochemical reactions in the cell. Altered CoA metabolism results in severe conditions such as pantothenate kinase-associated neurodegeneration (PKAN) in which a reduction of the activity of pantothenate kinase isoform 2 (PANK2) present in CoA biosynthesis in the brain consequently lowers the level of CoA in this organ. In order to develop a new drug aimed at restoring the sufficient amount of CoA in the brain of PKAN patients, we looked at its turnover. We report here the results of two experiments that enabled us to measure the half-life of pantothenic acid, free CoA (CoASH) and acetylCoA in the brains and livers of male and female C57BL/6N mice, and total CoA in the brains of male mice. We administered (intrastriatally or orally) a single dose of a [13C3-15N-18O]-labelled coenzyme A precursor (fosmetpantotenate or [13C3-15N]-pantothenic acid) to the mice and measured, by liquid chromatography-mass spectrometry, unlabelled- and labelled-coenzyme A species appearance and disappearance over time. We found that the turnover of all metabolites was faster in the liver than in the brain in both genders with no evident gender difference observed. In the oral study, the CoASH half-life was: 69 ± 5 h (male) and 82 ± 6 h (female) in the liver; 136 ± 14 h (male) and 144 ± 12 h (female) in the brain. AcetylCoA half-life was 74 ± 9 h (male) and 71 ± 7 h (female) in the liver; 117 ± 13 h (male) and 158 ± 23 (female) in the brain. These results were in accordance with the corresponding values obtained after intrastriatal infusion of labelled-fosmetpantotenate (CoASH 124 ± 13 h, acetylCoA 117 ± 11 and total CoA 144 ± 17 in male brain).

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The Pathophysiological Role of CoA

Cited by 76 publications

References 187 publications

Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

Coenzyme a Biochemistry: From Neurodevelopment to Neurodegeneration

Turnover rate of coenzyme A in mouse brain and liver

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