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Current Protein & Peptide Science 2016Metabolic pathways that extract energy from carbon compounds are essential for an organism's survival. Therefore, inhibition of enzymes in these pathways represents a... (Review)
Review
Metabolic pathways that extract energy from carbon compounds are essential for an organism's survival. Therefore, inhibition of enzymes in these pathways represents a potential therapeutic strategy to combat parasitic infections. However, the high degree of similarity between host and parasite enzymes makes this strategy potentially difficult. Nevertheless, several existing drugs to treat infections by parasitic helminths (worms) target metabolic enzymes. These include the trivalent antimonials that target phosphofructokinase and Clorsulon that targets phosphoglycerate mutase and phosphoglycerate kinase. Glycolytic enzymes from a variety of helminths have been characterised biochemically, and some inhibitors identified. To date none of these inhibitors have been developed into therapies. Many of these enzymes are externalised from the parasite and so are also of interest in the development of potential vaccines. Less work has been done on tricarboxylic acid cycle enzymes and oxidative phosphorylation complexes. Again, while some inhibitors have been identified none have been developed into drug-like molecules. Barriers to the development of novel drugs targeting metabolic enzymes include the lack of experimentally determined structures of helminth enzymes, lack of direct proof that the enzymes are vital in the parasites and lack of cell culture systems for many helminth species. Nevertheless, the success of Clorsulon (which discriminates between highly similar host and parasite enzymes) should inspire us to consider making serious efforts to discover novel anthelminthics, which target metabolic enzymes.
Topics: Animals; Citric Acid Cycle; Drug Discovery; Glycolysis; Helminths; Humans; Molecular Targeted Therapy; Oxidative Phosphorylation
PubMed: 26983888
DOI: 10.2174/1389203717999160226180733 -
Biomolecules Feb 2022Cancer metastasis is the leading cause of cancer-related mortality and the process of the epithelial-to-mesenchymal transition (EMT) is crucial for cancer metastasis....
Cancer metastasis is the leading cause of cancer-related mortality and the process of the epithelial-to-mesenchymal transition (EMT) is crucial for cancer metastasis. Both partial and complete EMT have been reported to influence the metabolic plasticity of cancer cells in terms of switching among the oxidative phosphorylation, fatty acid oxidation and glycolysis pathways. However, a comprehensive analysis of these major metabolic pathways and their associations with EMT across different cancers is lacking. Here, we analyse more than 180 cancer cell datasets and show the diverse associations of these metabolic pathways with the EMT status of cancer cells. Our bulk data analysis shows that EMT generally positively correlates with glycolysis but negatively with oxidative phosphorylation and fatty acid metabolism. These correlations are also consistent at the level of their molecular master regulators, namely AMPK and HIF1α. Yet, these associations are shown to not be universal. The analysis of single-cell data for EMT induction shows dynamic changes along the different axes of metabolic pathways, consistent with general trends seen in bulk samples. Further, assessing the association of EMT and metabolic activity with patient survival shows that a higher extent of EMT and glycolysis predicts a worse prognosis in many cancers. Together, our results reveal the underlying patterns of metabolic plasticity and heterogeneity as cancer cells traverse through the epithelial-hybrid-mesenchymal spectrum of states.
Topics: Epithelial-Mesenchymal Transition; Glycolysis; Humans; Metabolic Networks and Pathways; Neoplasms; Oxidative Phosphorylation
PubMed: 35204797
DOI: 10.3390/biom12020297 -
The Japanese Journal of Physiology Dec 2004A computer model of oxidative phosphorylation was developed in isolated muscle mitochondria [Korzeniewski and Mazat: Biochem J 319: 143-148, 1996] and in intact skeletal... (Review)
Review
A computer model of oxidative phosphorylation was developed in isolated muscle mitochondria [Korzeniewski and Mazat: Biochem J 319: 143-148, 1996] and in intact skeletal muscle [Korzeniewski and Zoladz: Biophys Chem 92: 17-34, 2001]. Within this model the dependence on different metabolite concentrations of the rate of each enzymatic reaction, process and flux is described by an appropriate kinetic equation. The changes of metabolite concentrations over time are described by a set of ordinary differential equations. The model has been very extensively tested by a comparison of computer simulations with a broad set of experimental results concerning various kinetic properties of the oxidative phosphorylation system. Next the model was used for theoretical studies on the regulation of oxidative phosphorylation in intact muscle cells. The model decidedly supports the so-called parallel-activation mechanism or each-step-activation mechanism of adjusting the rate of ATP supply to the current energy demand [Korzeniewski: Biochem J 330: 1189-1195, 1998; Korzeniewski: Biochem J 375: 799-804, 2003]. Because of this mechanism, not only ATP usage, but also the substrate dehydrogenation system and all oxidative phosphorylation complexes (complex I, complex III, complex IV, ATP synthase, ATP/ADP carrier, phosphate carrier) are directly (and not by changes in metabolite concentrations) activated by some intracellular factor(s) related to muscle contraction, probably by calcium ions, during the transition from rest to work. This mechanism is able to account for several kinetic properties of oxidative phosphorylation that cannot be explained by other mechanisms postulated in the literature. Thus the discussed kinetic model of oxidative phosphorylation has appeared to be a very useful research tool.
Topics: Animals; Computer Simulation; Humans; Models, Biological; Muscle, Skeletal; Oxidative Phosphorylation
PubMed: 15760482
DOI: 10.2170/jjphysiol.54.511 -
Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation.Biophysical Journal Feb 2016Competing models of mitochondrial energy metabolism in the heart are highly disputed. In addition, the mechanisms of reactive oxygen species (ROS) production and...
Competing models of mitochondrial energy metabolism in the heart are highly disputed. In addition, the mechanisms of reactive oxygen species (ROS) production and scavenging are not well understood. To deepen our understanding of these processes, a computer model was developed to integrate the biophysical processes of oxidative phosphorylation and ROS generation. The model was calibrated with experimental data obtained from isolated rat heart mitochondria subjected to physiological conditions and workloads. Model simulations show that changes in the quinone pool redox state are responsible for the apparent inorganic phosphate activation of complex III. Model simulations predict that complex III is responsible for more ROS production during physiological working conditions relative to complex I. However, this relationship is reversed under pathological conditions. Finally, model analysis reveals how a highly reduced quinone pool caused by elevated levels of succinate is likely responsible for the burst of ROS seen during reperfusion after ischemia.
Topics: Adenosine Triphosphate; Biocatalysis; Cell Hypoxia; Models, Biological; Oxidative Phosphorylation; Reactive Oxygen Species
PubMed: 26910433
DOI: 10.1016/j.bpj.2015.09.036 -
Journal of Huntington's Disease 2022Mitochondria (MT) are energy "powerhouses" of the cell and the decline in their function from oxidative damage is strongly correlated in many diseases. To suppress...
BACKGROUND
Mitochondria (MT) are energy "powerhouses" of the cell and the decline in their function from oxidative damage is strongly correlated in many diseases. To suppress oxygen damage, we have developed and applied XJB-5-131 as a targeted platform for neutralizing reactive oxygen species (ROS) directly in MT. Although the beneficial activity of XJB-5-131 is well documented, the mechanism of its protective effects is not yet fully understood.
OBJECTIVE
Here, we elucidate the mechanism of protection for XJB-5-131, a mitochondrial targeted antioxidant and electron scavenger.
METHODS
The Seahorse Flux Analyzer was used to probe the respiratory states of isolated mouse brain mitochondria treated with XJB-5-131 compared to controls.
RESULTS
Surprisingly, there is no direct impact of XJB-5-131 radical scavenger on the electron flow through the electron transport chain. Rather, XJB-5-131 is a mild uncoupler of oxidative phosphorylation. The nitroxide moiety in XJB-5-131 acts as a superoxide dismutase mimic, which both extracts or donates electrons during redox reactions. The electron scavenging activity of XJB-5-131 prevents the leakage of electrons and reduces formation of superoxide anion, thereby reducing ROS.
CONCLUSION
We show here that XJB-5-131 is a mild uncoupler of oxidative phosphorylation in MT. The mild uncoupling property of XJB-5-131 arises from its redox properties, which exert a protective effect by reducing ROS-induced damage without sacrificing energy production. Because mitochondrial decline is a common and central feature of toxicity, the favorable properties of XJB-5-131 are likely to be useful in treating Huntington's disease and a wide spectrum of neurodegenerative diseases for which oxidative damage is a key component. The mild uncoupling properties of XJB-5-131 suggest a valuable mechanism of action for the design of clinically effective antioxidants.
Topics: Animals; Cyclic N-Oxides; Huntington Disease; Mice; Oxidative Phosphorylation; Oxidative Stress; Reactive Oxygen Species
PubMed: 35404288
DOI: 10.3233/JHD-220539 -
Trends in Plant Science Jan 2024The mitochondrial NADH-dehydrogenase complex of the respiratory chain, known as complex I, includes a carbonic anhydrase (CA) module attached to its membrane arm on the... (Review)
Review
The mitochondrial NADH-dehydrogenase complex of the respiratory chain, known as complex I, includes a carbonic anhydrase (CA) module attached to its membrane arm on the matrix side in protozoans, algae, and plants. Its physiological role is so far unclear. Recent electron cryo-microscopy (cryo-EM) structures show that the CA module may directly provide protons for translocation across the inner mitochondrial membrane at complex I. CAs can have a central role in adjusting the proton concentration in the mitochondrial matrix. We suggest that CA anchoring in complex I represents the original configuration to secure oxidative phosphorylation (OXPHOS) in the context of early endosymbiosis. After development of 'modern mitochondria' with pronounced cristae structures, this anchoring became dispensable, but has been retained in protozoans, algae, and plants.
Topics: Carbonic Anhydrases; Oxidative Phosphorylation; Mitochondria; Plants; Hydrogen-Ion Concentration
PubMed: 37599162
DOI: 10.1016/j.tplants.2023.07.007 -
Physiological Reports Jun 2023Acute aerobic exercise increases the number and proportions of circulating peripheral blood mononuclear cells (PMBC) and can alter PBMC mitochondrial bioenergetics. In...
Acute aerobic exercise increases the number and proportions of circulating peripheral blood mononuclear cells (PMBC) and can alter PBMC mitochondrial bioenergetics. In this study, we aimed to examine the impact of a maximal exercise bout on immune cell metabolism in collegiate swimmers. Eleven (7 M/4F) collegiate swimmers completed a maximal exercise test to measure anaerobic power and capacity. Pre- and postexercise PBMCs were isolated to measure the immune cell phenotypes and mitochondrial bioenergetics using flow cytometry and high-resolution respirometry. The maximal exercise bout increased circulating levels of PBMCs, particularly in central memory (KLRG1+/CD57-) and senescent (KLRG1+/CD57+) CD8+ T cells, whether measured as a % of PMBCs or as absolute concentrations (all p < 0.05). At the cellularlevel, the routine oxygen flow (IO [pmol·s ·10 PBMCs ]) increased following maximal exercise (p = 0.042); however, there were no effects of exercise on the IO measured under the LEAK, oxidative phosphorylation (OXPHOS), or electron transfer (ET) capacities. There were exercise-induced increases in the tissue-level oxygen flow (IO [pmol·s ·mL blood ]) for all respiratory states (all p < 0.01), except for the LEAK state, after accounting for the mobilization of PBMCs. Future subtype-specific studies are needed to characterize further maximal exercise's true impact on immune cell bioenergetics.
Topics: Leukocytes, Mononuclear; Mitochondria; Oxidative Phosphorylation; Exercise; Oxygen
PubMed: 37312242
DOI: 10.14814/phy2.15753 -
Biochimica Et Biophysica Acta Aug 2016The Crabtree and Warburg effects are two well-known deviations of cell energy metabolism that will be described herein. A number of hypotheses have been formulated... (Review)
Review
The Crabtree and Warburg effects are two well-known deviations of cell energy metabolism that will be described herein. A number of hypotheses have been formulated regarding the molecular mechanisms leading to these cellular energy metabolism deviations. In this review, we will focus on the emerging notion that metabolite-induced regulations participate in the induction of these effects. All throughout this review, it should be kept in mind that no regulatory mechanism is exclusive and that it may vary in cancer cells owing to different cell types or oncogenic background. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
Topics: Cell Respiration; Fructosediphosphates; Fructosephosphates; Glucose; Glucose-6-Phosphate; Glycolysis; Humans; Neoplasms; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; Tumor Cells, Cultured
PubMed: 27066942
DOI: 10.1016/j.bbabio.2016.03.034 -
Journal of Applied Physiology... May 2021Exercise often causes skeletal muscle hyperthermia, likely resulting in decreased efficiency of mitochondrial respiration. We hypothesized that athletic conditioning...
Exercise often causes skeletal muscle hyperthermia, likely resulting in decreased efficiency of mitochondrial respiration. We hypothesized that athletic conditioning would improve mitochondrial tolerance to hyperthermia. Skeletal muscle biopsies were obtained from six Alaskan sled dogs under light general anesthesia before and after a full season of conditioning and racing, and respiration of permeabilized muscle fibers was measured at 38, 40, 42, and 44°C. There was no effect of temperature on phosphorylating respiration, and athletic conditioning increased maximal phosphorylating respiration by 19%. Leak respiration increased and calculated efficiency of oxidative phosphorylation decreased with increasing incubation temperature, and athletic conditioning resulted in higher leak respiration and lower calculated oxidative phosphorylation efficiency at all temperatures. Conditioning increased skeletal muscle expression of putative mitochondrial leak pathways adenine nucleotide transporter 1 and uncoupling protein 3, both of which were correlated with the magnitude of leak respiration. We conclude that athletic conditioning in elite canine endurance athletes results in increased capacity for mitochondrial proton leak that potentially reduces maximal mitochondrial membrane potential during periods of high oxidative phosphorylation. This effect may provide a mechanistic explanation for previously reported decreases in exercise-induced muscle damage in well-conditioned subjects. Athletic conditioning is expected to increase exercise capacity through improved function of cardiopulmonary and musculoskeletal tissues. Our finding of decreased calculated efficiency of skeletal muscle mitochondria in one of the premier mammalian athletes suggests that this mandate for improved function may take the form of sacrificing capacity for maximal oxidative phosphorylation to minimize exercise-induced muscle damage caused by mitochondrial oxidative stress.
Topics: Animals; Dogs; Hyperthermia; Mitochondria, Muscle; Muscle, Skeletal; Oxidative Phosphorylation; Oxygen Consumption
PubMed: 33661725
DOI: 10.1152/japplphysiol.00969.2020 -
Cell Cycle (Georgetown, Tex.) Sep 2016
Topics: Glycolysis; Humans; Mitochondria; Neoplasms; Oxidative Phosphorylation
PubMed: 27362787
DOI: 10.1080/15384101.2016.1204850