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Nitric Oxide as a Signaling Molecule in the Systemic Inflammatory Response to LPS
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Proteins with thiol-containing residues (e.g., cysteines) at or near their active sites (e.g., glyceraldehyde-3-phosphate dehydrogenase) comprise some of the more sensitive targets of NO modification (13,14). Metalloproteins, especially those containing heme-metal complexes (e.g., guanylate cyclase) or iron-sulfur clusters (e.g., aconitase) (15,16), are particularly sensitive to reactions with NOx. Attack of metal-sulfur clusters not only leads to the modification of protein function but the release of transition metals (17) that catalyze Fenton-like reactions to form even more toxic radicals (e.g., OH·). It is important to appreciate that nucleophilic attack of proteins by NO does not always lead to protein inactivation. The activation of the enzyme guanylate cyclase by the binding of NO to its heme iron (18,19) is a model for NO-mediated cell signaling. Similarly, the constitutively active cellular enzyme aconitase is converted to an RNA-binding regulatory protein following NO-induced disassembly of its core iron-sulfur cluster (16).
Effector Mechanisms for Macrophage-Induced Cytostasis and Cytolysis of Tumor Cells
Published in Gloria H. Heppner, Amy M. Fulton, Macrophages and Cancer, 2019
Carleton C. Stewart, Anita P. Stevenson, John Hibbs
As shown in Figure 10, aconitase was inhibited prior to inhibition of complex I and complex II of the mitochondrial electron-transport system. However, inhibition of aconitase activity may not have a significant effect on mitochondrial respiration and ATP synthesis. As shown in Table 1, aconitase activity was completely inhibited in target cells that had been co-cultivated with activated macrophages for 6 hr, but endogenous coupled and uncoupled respiration was unchanged from that measured in control target cells.44 These results suggest that a citric acid cycle block at the level of aconitase, which occurs early in the cocultivation period, does not inhibit mitochondrial respiration and that as long as complex I and complex II are still functional, endogenous substrates are able to circumvent the aconitase block. However, after 24 hr of co-cultivation of target cells, both endogenous coupled and uncoupled respiration was markedly inhibited. In addition, when complex I and complex II becomes inhibited, the cell loses 95% of its energy production potential. This would lead to cell death unless compensated for by increased glycolysis and the presence of high glucose in the medium. We propose that the observed variation in time to the expression of death is a function of how long the cell can survive on this severely limited energy production and its ability to restore respiratory function (or initiate glycolysis) when macrophages can no longer produce the appropriate effector molecules resulting in iron release.
Structure, Function and Evolutionary Aspects of Mitochondria
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Puja Agarwal, Mehali Mitra, Sujit Roy
The whole process is catalyzed by the multienzyme complex pyruvate dehydrogenase. The acetyl-CoA produced then enters in the citric acid cycle or TCA cycle (Fig. 2). All the enzymes of TCA cycle resides in the mitochondrial matrix except succinate dehydrogenase, which enters through inner mitochondrial membrane (Friedman and Nunnari, 2014; Nunnari and Suomalainen, 2012). In the first step of TCA cycle the acetyl CoA condenses with a 4 carbon molecules oxaloacetate and gives rise to citrate, which is a six carbon molecule (Fermie et al., 2004). This step is catalyzed by citrate synthase. In every cycle this citrate molecule ultimately decreases at chain length giving rise to 4 carbon oxaloacetate molecule so that it can condense with another acetyl-CoA molecule and keeps the cycle going (Rowland and Voeltz, 2012). The two carbons that are released during TCA cycle are completely oxidized to CO2. The citrate molecule is oxidized to isocitrate by aconitase in the next step. This isocitrate is then converted to a 5-Carbon molecule α-Ketoglutarate along with reduction of a NAD+ to NADH. In this step one carbon molecule released converts to CO2. In the whole cycle four reactions are there in which pair of electrons are transferred to electron accepting co-enzyme. In three of these reactions NAD+ get reduced to NADH and in another reaction FAD gets reduced to FADH2. The α-Ketoglutarate then gives rise to a 4 carbon molecule succinyl-CoA by α-Ketoglutarate dehydrogenase. This step involves a HS-CoA and another molecule of CO2 releases from this step. This succinate is ultimately converted to oxaloacetate via fumarate and malate. The rest of the enzymes involved are succinyl Co-A synthase, Succinate dehydrogenase, fumerase and malate dehydrogenase. The overall equation for the TCA Cycle can be summarized in the following two step reactions:
A deep dive into future therapies for microcytic anemias and clinical considerations
Published in Expert Review of Hematology, 2023
François Rodrigues, Tereza Coman, Guillemette Fouquet, Francine Côté, Geneviève Courtois, Thiago Trovati Maciel, Olivier Hermine
Homeostasis of cellular iron is modulated by post-transcriptional regulations of TfR1 and ferritin, the main intracellular iron storing protein. When levels of cytosolic iron decrease, aconitase is converted into iron-regulatory protein 1 (IRP1), while IRP2 iron-dependent degradation is inhibited. IRPs bind an iron-responsive element (IRE) in the 3’ untranslated region of TfR1 mRNA, increasing its stability and allowing the cell to import more transferrin. IRPs also bind the 5-UTR of ferritin mRNA, inhibiting ferritin synthesis [8]. IRPs are ubiquitously expressed in human tissues [9]. Mutations leading to constitutive IRP1 activation in humans trigger a paradoxical microcytic anemia because the mRNA of ALAS2, a key heme synthesis enzyme, contains an IRE allowing IRP1 to inhibit its translation [10]. Meanwhile, biallelic loss-of-function variants of IRP2 have recently been described in a patient presenting with microcytic anemia and severe neurodegeneration resembling neuroferritinopathy, where excess intracellular ferritin leads to iron accumulation and reduced availability for metabolic purposes [11].
A novel treatment strategy to prevent Parkinson’s disease: focus on iron regulatory protein 1 (IRP1)
Published in International Journal of Neuroscience, 2023
Thomas M. Berry, Ahmed A. Moustafa
Iron-sulfur cluster biogenesis is a process that involves many steps [38]. Even with normal levels of iron iron-sulfur biogenesis can be dysregulated. Dysregulation of the acyl carrier protein can impair iron-sulfur cluster biogenesis [39,40]. Many illnesses could be due to dysregulation of iron-sulfur cluster biogenesis [41]. Iron-sulfur cluster biogenesis dysregulations result in mitochondrial iron overload [42]. Research points to there being mitochondrial overload in both Parkinson’s disease and Friedreich ataxia [43]. How iron-sulfur cluster biogenesis could be dysregulated in PD is not completely clear. A way that iron-sulfur cluster biogenesis could be dysregulated in PD is via dysregulation of the acyl carrier protein. Difficulties in iron-sulfur cluster formation can be compensated for by supplemental iron. Supplemental iron can increase activity of aconitase 1(ACO1) [44], which is an iron-sulfur protein. Deficiency states in terms of nutrients can arise when there are extraordinary demands for nutrients. Individuals with PD could have extraordinary demands for iron.
Multi-organ system failure secondary to difluoroethane toxicity in a patient “huffing” air duster: a case report
Published in Journal of Addictive Diseases, 2022
Benjamin Fogelson, David Qu, Milind Bhagat, Paul R Branca
Biochemically, 1,1-difluoroethane has the potential to affect any organ system and cause multi-organ system failure. The mechanism of organ injury is primarily due to fluorocitrate accumulation.18 Difluoroethane is metabolized into fluoroacetate and then converted to fluorocitrate by the citric acid cycle in place of acetate.18 Through competitive inhibition of aconitase, fluorocitrate prevents the conversion of citrate to isocitrate, ultimately disrupting cellular energy production.18 Kumar et al. presented a case of 1,1-difluoroethane induced acute myocardial injury with concomitant acute liver failure and renal injury in a patient with a two-day history of “huffing” household aerosol products.14 Our patient, with at least a three-month history of daily “huffing” air duster, presented with multi-organ system failure with evidence of myocardial injury, hepatic failure, and acute kidney injury with severe metabolic acidosis. Additionally, our patient was found to have severe hypocalcemia associated with her acute renal failure and 1,1-difluoroethane toxicity. The mechanism of profound hypocalcemia in patients with 1,1-difluoroethane toxicity is secondary to chelation of calcium by isocitrate.18 Fortunately, our patient recovered from her metabolic derangements and end organ damage with aggressive fluid resuscitation, bicarbonate infusion, and electrolyte replacement.