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New Developments in Drug Treatment
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Alexander S. Pym, Camus Nimmo, James Millard
ATP synthase is an attractive drug target because it is essential, and ATP is required even in persistent bacterial states.13 Therefore it was not surprising to find that bedaquiline is active on dividing and non-dividing bacteria14 and displays time-dependent bactericidal activity both in vitro and in vivo. It has been extensively studied in the murine model and has emerged as a potential key component of new drug regimens.15 It is highly active given as mono-therapy and can substitute for any of the three first-line drugs,10,16 exhibits strong synergy with PZA17 and can shorten MDR-TB treatment.18 With the aim of developing a universal regimen, active against drug-susceptible and -resistant organisms various combinations of pretomanid (PA-824), clofazimine, sutezolid, bedaquiline, rifapentine and pyrazinamide were evaluated in a long-term mouse model. In terms of relapse-free cure after SCC, only regimens with bedaquiline were successful indicating its importance to new regimens.15
Introduction to lactic acidemias
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Energy conversion takes place in mitochondria in which the exergonic oxidation/reduction reactions of the electron transport chain, as in chloroplasts and bacteria, are coupled to the endergonic synthesis of adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate [14]. The electron flow generates a proton motive force. The ATP synthase is a large asymmetric enzyme complex of an F0F1 structure, in which the F0 is a hydrophobic, membrane-embedded unit that serves as a proton channel, while the F1 contains the nucleotide binding sites and catalytic sites for ATP synthesis. When solubilized and uncoupled from its F0 energy source, the F1 is capable of ATP hydrolysis, and this is why it is referred to as an ATPase.
Carbohydrate supplementation
Published in Jay R Hoffman, Dietary Supplementation in Sport and Exercise, 2019
Parker N Hyde, Richard A LaFountain, Carl M Maresh
Next in the process of glucose metabolism is the citric acid (TCA) cycle. Pyruvate molecules from glycolysis are transported into the mitochondria where they are first converted into acetyl-CoA and then fed into the pathway. A series of enzymatic reactions comprise the TCA cycle, where it produces three NADH+H, one FADH2 and one guanosine triphosphate (GTP) which is later converted to ATP. Following along in the oxidative metabolism of carbohydrates is the electron transport chain, which uses oxidative phosphorylation to produce ATP. This process is a series of coupled redox reactions that take advantage of the reducing capacity of NADH+H and FADH2. Briefly, these reducing agents donate electrons to the electron transport chain in order to generate a hydrogen ion gradient. The energy released from ions traveling down the concentration gradient helps to “power” ATP synthase to produce ATP. While the TCA cycle and the electron transport chain are able to produce large volumes of ATP molecules, the rate is significantly slower than glycolysis. When athletes are performing high work capacity events or performing exercise at a high intensity these two oxidative pathways are not able to keep up with energetic demands.
Passive heat stress induces mitochondrial adaptations in skeletal muscle
Published in International Journal of Hyperthermia, 2023
Erik D. Marchant, W. Bradley Nelson, Robert D. Hyldahl, Jayson R. Gifford, Chad R. Hancock
Oxidative phosphorylation is the process by which the majority of ATP is produced in muscle cells. This process involves a series of redox reactions which result in electrons being transferred through protein complexes (referred to as complexes I-IV), ultimately reacting with molecular oxygen. These redox reactions are coupled with the transfer of protons (H+ ions) out of the matrix, resulting in an increase in membrane potential. Protons then flow down a gradient and drive the production of ATP, catalyzed by ATP synthase. In response to changes in energy demand, like muscle disuse or endurance exercise training, skeletal muscle is able to increase or decrease its capacity to perform oxidative phosphorylation via changes in the density of mitochondrial enzymes in existing mitochondria and/or alteration of mitochondrial volume [3,7].
scRNA-seq reveals ATPIF1 activity in control of T cell antitumor activity
Published in OncoImmunology, 2022
Genshen Zhong, Qi Wang, Ying Wang, Ying Guo, Meiqi Xu, Yaya Guan, Xiaoying Zhang, Minna Wu, Zhishan Xu, Weidong Zhao, Hongkai Lian, Hui Wang, Jianping Ye
ATPIF1 (IF1) is an inhibitory protein of F1Fo-ATP synthase (ATP synthase, Complex V) that catalyzes ATP production by phosphorylation of ADP at the expense of mitochondrial potential in the energy-enriched environment.9 The ATP synthase hydrolyzes ATP in the energy-deficient conditions to protect cells from apoptosis, in which the energy is used to maintain the mitochondrial potential. Both activities of the ATP synthase are regulated by ATPIF1 through a physical interaction.9–11 Additionally, ATPIF1 is vital in the maintenance of mitochondrial structure.12 It was reported that global ATPIF1 deficiency did not impact the mouse growth and breeding.13 However, ATPIF1 inactivation protected mice from hyperglycemia in diet-induced obese mice and attenuated colitis in the mouse model.14,15 ATPIF1 activity has been investigated in the regulation of metabolism in the neuronal cells,16 red blood cells,17 epithelial cells,18 hepatocytes,19 and tumor cells.20 However, its role remains unclear in lymphocytes.
Contributing role of mitochondrial energy metabolism on platelet adhesion, activation and thrombus formation under blood flow conditions
Published in Platelets, 2022
Noriko Tamura, Shinichi Goto, Hideo Yokota, Shinya Goto
The contributing roles of mitochondrial function in platelet adhesion, activation, and thrombus formation were shown by three of mitochondrial function inhibitors with different mechanisms of action. The FCCP is an uncoupler of mitochondrial oxidative phosphorylation [29]. Antimycin A blocks the function of cytochrome-c reductase in mitochondrial complex III [5,30,31]. Oligomycin is a specific inhibitor of F1F0-ATP synthase at mitochondria. All three inhibitors worked at the dose tested because the glucose consumption rates increased in their presence. Thus, our results of inhibited rapid increase in [Ca2+]i upon adhering VWF is likely dependent on the inhibition of mitochondrial function. Mitochondrial function is important for cell signaling and death [32]; one may argue that the reduced rise in [Ca2+]i in platelets adhering to VWF may be based on the vital status of platelets in the presence of mitochondrial functional blockers. To avoid potential cell death induced by the presence of mitochondrial functional blockers, we conducted all experiments within 2 h after drawing blood. Moreover, our experimental results that the addition of mitochondrial functional blockers did not influence platelet adhesion and thrombus formation support the notion that a substantial number of platelets are still alive even in the presence of the three mitochondrial functional blockers we used in our experiments. However, further investigations are necessary for a precise understanding of the role of mitochondria and the rapid increase in [Ca2+]i.