scholarly journals Why is cyanide acutely lethal at very low doses?

2019 ◽  
Author(s):  
Kelath Murali Manoj
Keyword(s):  
Reactive Oxygen Species ◽  
Oxygen Consumption ◽  
Oxygen Transport ◽  
Atp Synthesis ◽  
Low Doses ◽  
Oxygen Species ◽  
Mitochondrial Cytochrome ◽  
Futile Cycles ◽  
New Hypothesis ◽  
Mitochondrial Cytochrome Oxidase

Cyanide is conventionally perceived as a binder of heme-Fe centers, disrupting oxygen transport by blood hemoglobin and mitochondrial cytochrome oxidase function. This explanation of toxicity would require millimolar (g/Kg dosage) concentration of cyanide, whereas it is lethal even at micromolar (mg/Kg dosage) ranges. It is long known that oxygen consumption by cells leads to the production of diffusible reactive oxygen species (DROS). Recently, DROS mediated catalytic/metabolic roles were proposed as a physiological source of heat and phosphorylation of ADP within mitochondria. In this purview, it is hypothesized herein that cyanide uses the catalytic DROS via futile cycles, stopping ATP-synthesis and thus killing cells. A quantitative mechanistic perspective delineating the old and new explanations is provided herein. Further, experimental modalities and predictable outcomes are detailed to test the new hypothesis.

scholarly journals The energetic cost of NNT-dependent ROS removal

2020 ◽  
Vol 295 (48) ◽  
pp. 16217-16218
Author(s):  
Nina Kaludercic ◽  
Fabio Di Lisa
Keyword(s):  
Reactive Oxygen Species ◽  
Oxygen Consumption ◽  
Cell Injury ◽  
Atp Synthesis ◽  
Energetic Cost ◽  
Oxygen Species ◽  
Oxygen Utilization ◽  
Mitochondrial Oxygen Consumption ◽  
High Nutrient ◽  
Ros Formation

Under conditions of high nutrient availability and low ATP synthesis, mitochondria generate reactive oxygen species (ROS) that must be removed to avoid cell injury. Among the enzymes involved in this scavenging process, peroxidases play a crucial role, using NADPH provided mostly by nicotinamide nucleotide transhydrogenase (NNT). However, scarce information is available on how and to what extent ROS formation is linked to mitochondrial oxygen consumption. A new study by Smith et al. shows that NNT activity maintains low ROS levels by means of a fine modulation of mitochondrial oxygen utilization.

Anesthetic Preconditioning Improves Adenosine Triphosphate Synthesis and Reduces Reactive Oxygen Species Formation in Mitochondria after Ischemia by a Redox Dependent Mechanism

2003 ◽  
Vol 98 (5) ◽  
pp. 1155-1163 ◽  
Author(s):  
Enis Novalija ◽  
Leo G. Kevin ◽  
Janis T. Eells ◽  
Michele M. Henry ◽  
David F. Stowe
Keyword(s):  
Reactive Oxygen Species ◽  
Cardiac Function ◽  
Adenosine Triphosphate ◽  
Reactive Oxygen ◽  
Atp Synthesis ◽  
Ros Generation ◽  
Oxygen Species ◽  
Protective Effects ◽  
Anesthetic Preconditioning ◽  
Species Formation

Background Mitochondrial changes that characterize the heart after anesthetic preconditioning (APC) or the mechanisms by which mitochondrial triggering factors lead to protection are unknown. This study hypothesized that generation of reactive oxygen species (ROS) during APC is required to initiate the mitochondrial protective effects, and that APC leads to improved mitochondrial electron transport chain function and cardiac function during reperfusion. Methods Isolated guinea pig hearts were subject to 30 min ischemia and 120 min reperfusion. Prior to ischemia hearts were either untreated (I/R), or treated with sevoflurane (APC), in the presence or absence of the ROS scavenger tiron (TIR), or the superoxide dismutase mimetic MnTBAP (TBAP). Intracellular ROS were measured by spectrofluorometry using the fluorescent probe dihydroethidium (DHE). In another series of experiments, using the same protocol, hearts were reperfused for only 5 min and removed for measurement of adenosine triphosphate (ATP) synthesis by luciferin-luciferase luminometry and ROS generation by dichlorohydro-fluorescein (DCF) fluorescence in isolated mitochondria. Results The APC improved cardiac function and reduced infarction. Tiron or MnTBAP abrogated the protection afforded by APC. Mitochondrial ATP synthesis was decreased by 70 +/- 3% after IR alone, by only 7 +/- 3% after APC, by 69 +/- 2% after APC+TIR, and by 71 +/- 3% after APC + TBAP. Mitochondrial ROS formation (DCF) increased by 48 +/- 3% after IR alone, by 0 +/- 2% after APC, by 43 +/- 4% after APC + TIR, and by 46 +/- 3% after APC + TBAP. ROS generation (DHE) was increased in I/R group at 5 and 120 min reperfusion. This was attenuated by APC but this protective effect was abrogated in APC + TIR and APC + TBAP groups. Conclusions The results indicate that ROS are central both in triggering and mediating APC, and that the mitochondrion is the target for these changes.

scholarly journals Low-DoseAronia melanocarpaConcentrate Attenuates Paraquat-Induced Neurotoxicity

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
A. J. Case ◽  
D. Agraz ◽  
I. M. Ahmad ◽  
M. C. Zimmerman
Keyword(s):  
Reactive Oxygen Species ◽  
Hydrogen Peroxide ◽  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Reactive Oxygen ◽  
High Dose ◽  
Low Doses ◽  
Oxygen Species ◽  
High Doses

Herbicides containing paraquat may contribute to the pathogenesis of neurodegenerative disorders such as Parkinson’s disease. Paraquat induces reactive oxygen species-mediated apoptosis in neurons, which is a primary mechanism behind its toxicity. We sought to test the effectiveness of a commercially available polyphenol-richAronia melanocarpa(aronia berry) concentrate in the amelioration of paraquat-induced neurotoxicity. Considering the abundance of antioxidants in aronia berries, we hypothesized that aronia berry concentrate attenuates the paraquat-induced increase in reactive oxygen species and protects against paraquat-mediated neuronal cell death. Using a neuronal cell culture model, we observed that low doses of aronia berry concentrate protected against paraquat-mediated neurotoxicity. Additionally, low doses of the concentrate attenuated the paraquat-induced increase in superoxide, hydrogen peroxide, and oxidized glutathione levels. Interestingly, high doses of aronia berry concentrate increased neuronal superoxide levels independent of paraquat, while at the same time decreasing hydrogen peroxide. Moreover, high-dose aronia berry concentrate potentiated paraquat-induced superoxide production and neuronal cell death. In summary, aronia berry concentrate at low doses restores the homeostatic redox environment of neurons treated with paraquat, while high doses exacerbate the imbalance leading to further cell death. Our findings support that moderate levels of aronia berry concentrate may prevent reactive oxygen species-mediated neurotoxicity.

Low doses of reactive oxygen species protect endothelial cells from apoptosis by increasing thioredoxin-1 expression

FEBS Letters ◽  
2004 ◽  
Vol 577 (3) ◽  
pp. 427-433 ◽  
Author(s):  
Judith Haendeler ◽  
Verena Tischler ◽  
Jörg Hoffmann ◽  
Andreas M. Zeiher ◽  
Stefanie Dimmeler
Keyword(s):  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Reactive Oxygen ◽  
Low Doses ◽  
Oxygen Species ◽  
Thioredoxin 1

scholarly journals Murburn precepts for aerobic respiration and homeostasis

2019 ◽  
Author(s):  
Kelath Murali Manoj ◽  
Nikolai Bazhin
Keyword(s):  
Reactive Oxygen Species ◽  
Free Energy ◽  
Membrane Potential ◽  
Atp Synthesis ◽  
Aerobic Respiration ◽  
Oxygen Species ◽  
Cellular Toxicity ◽  
Origin And Evolution ◽  
Selectivity Control ◽  
Ros Reactive Oxygen Species

Transformed Gibbs free energy values of respiratory reactions are calculated to address the spontaneity, selectivity, control, and efficiency of oxidative phosphorylation. We present tangible explanations for ubiquinone’s role mitochondria, HCN > H2S order of cellular toxicity in aerobes and why oxygen inhibits anaerobes. Our data/arguments highlight the significance of proton deficiency in NADH/mitochondria and link the ‘oxygen → ROS (reactive oxygen species) → water’ metabolic pathway to the macroscopic physiologies of ATP-synthesis, trans-membrane potential, thermogenesis, and homeostasis. This ‘murburn perspective’ affords a probabilistically and thermodynamically viable precept for the origin and evolution of the ‘working logic’ of oxygen-centric life.

scholarly journals Solanesyl Diphosphate Synthase, an Enzyme of the Ubiquinone Synthetic Pathway, Is Required throughout the Life Cycle of Trypanosoma brucei

2013 ◽  
Vol 13 (2) ◽  
pp. 320-328 ◽  
Author(s):  
De-Hua Lai ◽  
Estefanía Poropat ◽  
Carlos Pravia ◽  
Malena Landoni ◽  
Alicia S. Couto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Reactive Oxygen Species ◽  
Drinking Water ◽  
Oxygen Consumption ◽  
Trypanosoma Brucei ◽  
Drug Target ◽  
Culture Medium ◽  
Oxygen Species ◽  
Content Type ◽  
Long Chain

ABSTRACTUbiquinone 9 (UQ9), the expected product of the long-chain solanesyl diphosphate synthase ofTrypanosoma brucei(TbSPPS), has a central role in reoxidation of reducing equivalents in the mitochondrion ofT. brucei. The ablation of TbSPPS gene expression by RNA interference increased the generation of reactive oxygen species and reduced cell growth and oxygen consumption. The addition of glycerol to the culture medium exacerbated the phenotype by blocking its endogenous generation and excretion. The participation of TbSPPS in UQ synthesis was further confirmed by growth rescue using UQ with 10 isoprenyl subunits (UQ10). Furthermore, the survival of infected mice was prolonged upon the downregulation of TbSPPS and/or the addition of glycerol to drinking water. TbSPPS is inhibited by 1-[(n-oct-1-ylamino)ethyl] 1,1-bisphosphonic acid, and treatment with this compound was lethal for the cells. The findings that both UQ9 and ATP pools were severely depleted by the drug and that exogenous UQ10 was able to fully rescue growth of the inhibited parasites strongly suggest that TbSPPS and UQ synthesis are the main targets of the drug. These two strategies highlight the importance of TbSPPS forT. brucei, justifying further efforts to validate it as a new drug target.

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