scholarly journals Murburn model of mitochondrial aerobic respiration is robust in comparison to the ‘chemiosmotic rotary or two-ion torsional’ ATP-synthesis proposals

2020 ◽  
Author(s):  
Daniel Andrew Gideon
Keyword(s):  
Oxidative Phosphorylation ◽  
Experimental Research ◽  
Atp Synthesis ◽  
Reaction Scheme ◽  
Aerobic Respiration ◽  
Evidence Based ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Paul Boyer ◽  
Intense Debate ◽  
Biophysical Chemistry

One of the most fundamental questions in biology pertains to how mechano-chemical energy is derived from metabolic fuels. In particular, how oxidation of NADH is linked to ATP synthesis in mitochondrial oxidative phosphorylation (mOxPhos) has been a topic of intense debate. Together, the Peter Mitchell-Paul Boyer proposals for mOxPhos are termed herein as “chemiosmotic rotary ATP synthesis” (or CRAS) model, which was recently defended/advocated by Pedro Silva in Biophysical Chemistry . Over the last two decades, Sunil Nath had questioned some aspects of the CRAS proposal, and made subtle alterations on the roles of Complex V and ions within the reaction scheme, and continues to advocate his framework as “two-ion torsional ATP synthesis” (abbreviated herein as TITAS) model in Biophysical Chemistry . Kelath Murali Manoj had revisited the data on the respiratory machinery’s structures/distributions and based on two-decades of evidence-based experimental research in redox enzymology of heme/flavin proteins, had formulated the murburn model for mOxPhos. In this work, the ETC-CRAS hypothesis and its off-shoot, the TITAS proposal, are questioned in the light of the convincing chemicophysical logic provided by the murburn hypothesis.

scholarly journals Rebutting Pedro J. Silva’s article in Biophysical Chemistry supporting Mitchell-Boyer’s ideas on bioenergetics and advocating murburn concept as a viable explanation for aerobic respiration and oxygenic photosynthesis

2020 ◽  
Author(s):  
Kelath Murali Manoj
Keyword(s):  
Oxidative Phosphorylation ◽  
Large Volume ◽  
Crucial Role ◽  
Atp Synthesis ◽  
Scientific Discourse ◽  
Oxygenic Photosynthesis ◽  
Aerobic Respiration ◽  
Bioenergetics Model ◽  
Critical Attention ◽  
Biophysical Chemistry

Over the last three years, I had pointed out the untenable nature of the proton-centric ‘chemiosmosis driven rotary ATP-synthesis (CRAS)’ explanation for Oxidative Phosphorylation (OxPhos). Recently, Pedro J. Silva (PJS) [Chemiosmotic misunderstandings (2020). Biophys. Chem. 264, 106424] afforded a part of our work his critical attention, but overlooked the large volume of evidence against CRAS and supporting the oxygen-centric murburn mechanism of OxPhos. In his article, PJS also posed some queries on our bioenergetics model. When I offered my rebuttal, the Editor of Biophysical Chemistry refused to publish it. Therefore, I have no other option than to publish the rebuttal as a preprint. Herein, I demonstrate the flaws and lacunae in PJS’s defense of CRAS hypothesis and answer his specific queries and defend the murburn explanation of mOxPhos. The current scientific discourse is crucial for correcting major historical errors in mitochondrial physiology and understanding oxygen’s crucial role in the powering chemistry of life.

scholarly journals Aerobic Respiration: Criticism of the Proton-centric Explanation Involving Rotary Adenosine Triphosphate Synthesis, Chemiosmosis Principle, Proton Pumps and Electron Transport Chain

2018 ◽  
Vol 11 ◽  
pp. 117862641881844 ◽  
Author(s):  
Kelath Murali Manoj
Keyword(s):  
Electron Transport ◽  
Adenosine Triphosphate ◽  
Electron Transport Chain ◽  
Atp Synthesis ◽  
Cellular Respiration ◽  
Aerobic Respiration ◽  
Proton Pumps ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Transport Chain ◽  
Interactive Dynamics

The acclaimed explanation for mitochondrial oxidative phosphorylation (mOxPhos, or cellular respiration) is a deterministic proton-centric scheme involving four components: Rotary adenosine triphosphate (ATP)-synthesis, Chemiosmosis principle, Proton pumps, and Electron transport chain (abbreviated as RCPE hypothesis). Within this write-up, the RCPE scheme is critically analyzed with respect to mitochondrial architecture, proteins’ distribution, structure-function correlations and their interactive dynamics, overall reaction chemistry, kinetics, thermodynamics, evolutionary logic, and so on. It is found that the RCPE proposal fails to explain key physiological aspects of mOxPhos in several specific issues and also in holistic perspectives. Therefore, it is imperative to look for new explanations for mOxPhos.

scholarly journals A Multi-Omics Study Revealing the Metabolic Effects of Estrogen in Liver Cancer Cells HepG2

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 455
Author(s):  
Minqian Shen ◽  
Mengyang Xu ◽  
Fanyi Zhong ◽  
McKenzie C. Crist ◽  
Anjali B. Prior ◽  
...  
Keyword(s):  
Cell Growth ◽  
Liver Cancer ◽  
Oxidative Phosphorylation ◽  
Hepg2 Cells ◽  
Atp Synthesis ◽  
Cell Number ◽  
Metabolic Effects ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Liver Cancers ◽  
Malignant Liver

Hepatocellular carcinoma (HCC) that is triggered by metabolic defects is one of the most malignant liver cancers. A much higher incidence of HCC among men than women suggests the protective roles of estrogen in HCC development and progression. To begin to understand the mechanisms involving estrogenic metabolic effects, we compared cell number, viability, cytotoxicity, and apoptosis among HCC-derived HepG2 cells that were treated with different concentrations of 2-deoxy-d-glucose (2-DG) that blocks glucose metabolism, oxamate that inhibits lactate dehydrogenase and glycolysis, or oligomycin that blocks ATP synthesis and mitochondrial oxidative phosphorylation. We confirmed that HepG2 cells primarily utilized glycolysis followed by lactate fermentation, instead of mitochondrial oxidative phosphorylation, for cell growth. We hypothesized that estrogen altered energy metabolism via its receptors to carry out its anticancer effects in HepG2 cells. We treated cells with 17β-estradiol (E2), 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) an estrogen receptor (ER) α (ERα) agonist, or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), an ERβ agonist. We then used transcriptomic and metabolomic analyses and identified differentially expressed genes and unique metabolite fingerprints that are produced by each treatment. We further performed integrated multi-omics analysis, and identified key genes and metabolites in the gene–metabolite interaction contributed by E2 and ER agonists. This integrated transcriptomic and metabolomic study suggested that estrogen acts on estrogen receptors to suppress liver cancer cell growth via altering metabolism. This is the first exploratory study that comprehensively investigated estrogen and its receptors, and their roles in regulating gene expression, metabolites, metabolic pathways, and gene–metabolite interaction in HCC cells using bioinformatic tools. Overall, this study provides potential therapeutic targets for future HCC treatment.

scholarly journals Acute toxicity of cyanide in aerobic respiration: Theoretical and experimental support for murburn explanation

2020 ◽  
Vol 11 (1) ◽  
pp. 32-56 ◽  
Author(s):  
Kelath Murali Manoj ◽  
Surjith Ramasamy ◽  
Abhinav Parashar ◽  
Daniel Andrew Gideon ◽  
Vidhu Soman ◽  
...  
Keyword(s):  
Heme Proteins ◽  
Atp Synthesis ◽  
Lethal Effect ◽  
Acute Onset ◽  
Aerobic Respiration ◽  
Oxygen Species ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Group Transfer ◽  
Water Formation

AbstractThe inefficiency of cyanide/HCN (CN) binding with heme proteins (under physiological regimes) is demonstrated with an assessment of thermodynamics, kinetics, and inhibition constants. The acute onset of toxicity and CN’s mg/Kg LD50 (μM lethal concentration) suggests that the classical hemeFe binding-based inhibition rationale is untenable to account for the toxicity of CN. In vitro mechanistic probing of CN-mediated inhibition of hemeFe reductionist systems was explored as a murburn model for mitochondrial oxidative phosphorylation (mOxPhos). The effect of CN in haloperoxidase catalyzed chlorine moiety transfer to small organics was considered as an analogous probe for phosphate group transfer in mOxPhos. Similarly, inclusion of CN in peroxidase-catalase mediated one-electron oxidation of small organics was used to explore electron transfer outcomes in mOxPhos, leading to water formation. The free energy correlations from a Hammett study and IC50/Hill slopes analyses and comparison with ligands $\left( {\text{CO}}/{{{{\text{H}}_{2}}\text{S}}/{\text{N}_{3}^{\text{-}}}\;}\; \right)$ provide insights into the involvement of diffusible radicals and proton-equilibriums, explaining analogous outcomes in mOxPhos chemistry. Further, we demonstrate that superoxide (diffusible reactive oxygen species, DROS) enables in vitro ATP synthesis from ADP+phosphate, and show that this reaction is inhibited by CN. Therefore, practically instantaneous CN ion-radical interactions with DROS in matrix catalytically disrupt mOxPhos, explaining the acute lethal effect of CN.

scholarly journals Thermodynamics, kinetics and reaction chemistry of aerobic respiration

2019 ◽  
Author(s):  
Kelath Murali Manoj ◽  
Nikolai Mikhailovich Bazhin
Keyword(s):  
Proton Transport ◽  
Atp Synthesis ◽  
Electrical Energy ◽  
Reaction Model ◽  
Cellular Respiration ◽  
Aerobic Respiration ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Definite Answer ◽  
Kinetics Of

Three fundamental queries are addressed on the thermodynamics of aerobic cellular respiration (viz. ATP-synthesis and thermogenesis)- (1) Can the energy of oxygen reduction be utilized for proton transport?, (2) Is the trans-membrane proton differential harness-able as a potential energy capable of doing useful work?, and (3) If the movement of a miniscule amount of mitochondrial protons could give rise to a potential of ~200 mV and if such an electrical energy could sponsor ATP-synthesis. Further, we provide a definite answer to a fourth question- what is the thermodynamic role of protons in the oxygen-centric scheme of aerobic respiration? Finally, we demonstrate that the rotary ATPase activity of Complex V cannot account for physiological ATP synthesis and establish that the murburn reaction model explains the kinetics of mitochondrial oxidative phosphorylation.

scholarly journals Substrate- and Calcium-Dependent Differential Regulation of Mitochondrial Oxidative Phosphorylation and Energy Production in the Heart and Kidney

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 131
Author(s):  
Xiao Zhang ◽  
Namrata Tomar ◽  
Sunil M. Kandel ◽  
Said H. Audi ◽  
Allen W. Cowley ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Respiration ◽  
Atp Synthesis ◽  
Heart Mitochondria ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Inhibitory Effects ◽  
Atp Production ◽  
Calcium Dependent ◽  
Palmitoyl Carnitine ◽  
Regulatory Effects

Mitochondrial dehydrogenases are differentially stimulated by Ca2+. Ca2+ has also diverse regulatory effects on mitochondrial transporters and other enzymes. However, the consequences of these regulatory effects on mitochondrial oxidative phosphorylation (OxPhos) and ATP production, and the dependencies of these consequences on respiratory substrates, have not been investigated between the kidney and heart despite the fact that kidney energy requirements are second only to those of the heart. Our objective was, therefore, to elucidate these relationships in isolated mitochondria from the kidney outer medulla (OM) and heart. ADP-induced mitochondrial respiration was measured at different CaCl2 concentrations in the presence of various respiratory substrates, including pyruvate + malate (PM), glutamate + malate (GM), alpha-ketoglutarate + malate (AM), palmitoyl-carnitine + malate (PCM), and succinate + rotenone (SUC + ROT). The results showed that, in both heart and OM mitochondria, and for most complex I substrates, Ca2+ effects are biphasic: small increases in Ca2+ concentration stimulated, while large increases inhibited mitochondrial respiration. Furthermore, significant differences in substrate- and Ca2+-dependent O2 utilization towards ATP production between heart and OM mitochondria were observed. With PM and PCM substrates, Ca2+ showed more prominent stimulatory effects in OM than in heart mitochondria, while with GM and AM substrates, Ca2+ had similar biphasic regulatory effects in both OM and heart mitochondria. In contrast, with complex II substrate SUC + ROT, only inhibitory effects on mitochondrial respiration was observed in both the heart and the OM. We conclude that the regulatory effects of Ca2+ on mitochondrial OxPhos and ATP synthesis are biphasic, substrate-dependent, and tissue-specific.

Dependence of Platelet Adenyl Cyclase System on Oxidative Phosphorylation

1975 ◽  
Vol 34 (01) ◽  
pp. 042-049 ◽  
Author(s):  
Shuichi Hashimoto ◽  
Sachiko Shibata ◽  
Bokro Kobayashi
Keyword(s):  
Cyclic Amp ◽  
Oxidative Phosphorylation ◽  
Sodium Succinate ◽  
Potassium Cyanide ◽  
Adenyl Cyclase ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Adenyl Cyclase Activity ◽  
Intact Rabbit ◽  
Adenyl Cyclase System ◽  
Cyclic Amp Synthesis

SummaryThe radioactive adenosine 3′,5′-monophosphate (cyclic AMP) level derived from 8-14C adenine in intact rabbit platelets decreased in the presence of mitochondrial inhibitor (potassium cyanide) or uncoupler (sodium azide), and markedly increased by the addition of NaF, monoiodoacetic acid (MIA), or 2-deoxy-D-glucose. The stimulative effect of the glycolytic inhibitors was distinctly enhanced by the simultaneous addition of sodium succinate. MIA did neither directly stimulate the adenyl cyclase activity nor inhibit the phosphodiesterase activity. These results suggest that cyclic AMP synthesis in platelets is closely linked to mitochondrial oxidative phosphorylation.

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