Acetyl-CoA the Key Factor for Survival or Death of Cholinergic Neurons in Course of Neurodegenerative Diseases

Szutowicz, Andrzej; Bielarczyk, Hanna; Jankowska-Kulawy, Agnieszka; Pawełczyk, Tadeusz; Ronowska, Anna

doi:10.1007/s11064-013-1060-x

Cited by 97 publications

(146 citation statements)

References 185 publications

(359 reference statements)

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“…Whereas mitochondrial HMGC generally feeds the synthesis of ketone bodies, its cytosolic counterpart is metabolized by 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR, the pharmacological target of statins) within the mevalonate pathway, which is essential in all cells for the production of sterols, ubiquinone (coenzyme Q 10 ), heme A, and other isoprenoids (Edwards and Ericsson, 1999). Finally, cytosolic acetyl-CoA is required for cell type-specific metabolic circuitries, such as the synthesis of acetylcholine, implying that the survival and activity of cholinergic neurons are particularly dependent on acetyl-CoA (Szutowicz et al, 2013).…”

Section: Generation Of Cytosolic Acetyl-coamentioning

confidence: 99%

Acetyl Coenzyme A: A Central Metabolite and Second Messenger

et al. 2015

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Acetyl-coenzyme A (acetyl-CoA) is a central metabolic intermediate. The abundance of acetyl-CoA in distinct subcellular compartments reflects the general energetic state of the cell. Moreover, acetyl-CoA concentrations influence the activity or specificity of multiple enzymes, either in an allosteric manner or by altering substrate availability. Finally, by influencing the acetylation profile of several proteins, including histones, acetyl-CoA controls key cellular processes, including energy metabolism, mitosis, and autophagy, both directly and via the epigenetic regulation of gene expression. Thus, acetyl-CoA determines the balance between cellular catabolism and anabolism by simultaneously operating as a metabolic intermediate and as a second messenger.

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Section: Generation Of Cytosolic Acetyl-coamentioning

confidence: 99%

Acetyl Coenzyme A: A Central Metabolite and Second Messenger

et al. 2015

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“…Neuronal death in AD is associated with progressive reductions in the neurotransmitter ACh (Francis et al, 1999) as well as the ACh precursor acetyl-CoA (Szutowicz et al, 2013). Current AD treatments include inhibitors of ACh degradation enzymes, or acetylcholinesterases (AChE) (Tabet, 2006).…”

Section: Introductionmentioning

confidence: 99%

Oxidative and nitrative stress in neurodegeneration

Cobb

Cole

2015

Neurobiology of Disease

234

180

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Aerobes require oxygen for metabolism and normal free radical formation. As a result, maintaining the redox homeostasis is essential for brain cell survival due to their high metabolic energy requirement to sustain electrochemical gradients, neurotransmitter release, and membrane lipid stability. Further, brain antioxidant levels are limited compared to other organs and less able to compensate for reactive oxygen and nitrogen species (ROS/RNS) generation which contribute oxidative/nitrative stress (OS/NS). Antioxidant treatments such as vitamin E, minocycline, and resveratrol mediate neuroprotection by prolonging the incidence of or reversing OS and NS conditions. Redox imbalance occurs when the antioxidant capacity is overwhelmed, consequently leading to activation of alternate pathways that remain quiescent under normal conditions. If OS/NS fails to lead to adaptation, tissue damage and injury ensue, resulting in cell death and/or disease. The progression of OS/NS-mediated neurodegeneration along with contributions from microglial activation, dopamine metabolism, and diabetes comprise a detailed interconnected pathway. This review proposes a significant role for OS/NS and more specifically, lipid peroxidation (LPO) and other lipid modifications, by triggering microglial activation to elicit a neuroinflammatory state potentiated by diabetes or abnormal dopamine metabolism. Subsequently, sustained stress in the neuroinflammatory state overwhelms cellular defenses and prompts neurotoxicity resulting in the onset or amplification of brain damage.

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“…This observation may be explained by the fact that differentiation of the SH-SY5Y cells is conducted towards the cholinergic phenotype. Highly differentiated cholinergic neurons are more sensitive to any cytotoxic factors (Szutowicz et al 2006, 2013). This phenomenon is explained by the fact that SH-SY5Y-DC use acetyl-CoA, a product of PDHC reaction, in the TCA and in acetylcholine synthesis.…”

Section: Discussionmentioning

confidence: 99%

Novel therapeutic compound acridine–retrotuftsin action on biological forms of melanoma and neuroblastoma

Cichorek

Ronowska

Gensicka-Kowalewska

et al. 2018

J Cancer Res Clin Oncol

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PurposeAs a continuation of our search for anticancer agents, we have synthesized a new acridine-retrotuftsin analog HClx9-[Arg(NO2)-Pro-Lys-Thr-OCH3]-1-nitroacridine (named ART) and have evaluated its activity against melanoma and neuroblastoma lines. Both tumors develop from cells (melanocytes, neurons) of neuroectodermal origin, and both are tumors with high heterogeneity and unsatisfactory susceptibility to chemotherapies. Thus, we analyzed the action of ART on pairs of biological forms of melanoma (amelanotic and melanotic) and neuroblastoma (dopaminergic and cholinergic) with regard to proliferation, mechanism of cell death, and effect on the activity of tricarboxylic acid cycle (TAC) enzymes.MethodsThe cytotoxicity of ART was evaluated by XTT and trypan blue tests. Cell death was estimated by plasma membrane structure changes (phosphatidylserine and calreticulin externalization), caspase activation, presence of ROS (reactive oxygen species), activity of tricarboxylic acid cycle enzymes (pyruvate dehydrogenase complex, aconitase, and isocitrate dehydrogenase), NAD level, and ATP level.ResultsART influences the biological forms of melanoma and neuroblastoma in different ways. Amelanotic (Ab) melanoma (with the inhibited melanogenesis, higher malignancy) and SHSY5Y neuroblastoma (with cholinergic DC cells) were especially sensitive to ART action. The Ab melanoma cells died through apoptosis, while, with SH-SY5Y-DC neuroblastoma, the number of cells decreased but not as a result of apoptosis. With Ab melanoma and SH-SY5Y-DC cells, a diminished activity of TAC enzymes was noticed, along with ATP/NAD depletion.ConclusionOur data show that the biological forms of certain tumors responded in different ways to the action of ART. As a combination of retrotuftsin and acridine, the compound can be an inducer of apoptotic cell death of melanoma, especially the amelanotic form. Although the mechanism of the interrelationships between energy metabolism and cell death is not fully understood, interference of ART with TAC enzymes could encourage the further investigation of its anticancer action.Electronic supplementary materialThe online version of this article (10.1007/s00432-018-2776-4) contains supplementary material, which is available to authorized users.

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Acetyl-CoA the Key Factor for Survival or Death of Cholinergic Neurons in Course of Neurodegenerative Diseases

Cited by 97 publications

References 185 publications

Acetyl Coenzyme A: A Central Metabolite and Second Messenger

Acetyl Coenzyme A: A Central Metabolite and Second Messenger

Oxidative and nitrative stress in neurodegeneration

Novel therapeutic compound acridine–retrotuftsin action on biological forms of melanoma and neuroblastoma

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