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Implication of Mitochondrial Coenzyme Q10 (Ubiquinone) in Alzheimer’s Disease *
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Sayantan Maitra, Dibyendu Dutta
Both the initiation and propagation stages of lipid peroxidation are hindered by ubiquinol. On the contrary, vitamin E acts exclusively as a chain-breaking antioxidant by inhibiting propagation. Indeed, ubiquinol emerges to accomplish both of these functions due to its expression in the hydrophobic region of the membrane phospholipid bilayer, where these reactions take place, and perhaps even more importantly, due to its access to a powerful enzymatic mechanism, the proton motive Q cycle, which is capable of regenerating ubiquinol from the ubisemiquinone radical [27,31].
Nutritional Ergogenic Aids: Introduction, Definitions and Regulatory Issues
Published in Ira Wolinsky, Judy A. Driskell, Nutritional Ergogenic Aids, 2004
Ira Wolinsky, Judy A. Driskell
The cell membrane mainly consists of phospholipids and proteins. It is believed that ubiquinol plays an important role in protecting the membrane from lipid peroxidation (deterioration). It may act as either an independent antioxidant or a co-antioxidant with vitamin E and C.5,20 It has been suggested that ubiquinol may prevent both the initiation and propagation of lipid peroxidation, possibly because of its lipidphilic property and location in the membrane that allows its access to the proton-motive Q cycle. Vitamin E acts exclusively in inhibition of the propagation of lipid peroxidation.8 After quenching a free radical, CoQ10 can be recycled within plasma membranes and cytosol by quinone reductase.5 It has also been shown that ubiquinol provides protection for proteins and DNA against oxidative damage.8
Altered Calcium Homeostasis in Old Neurons
Published in David R. Riddle, Brain Aging, 2007
Another potential target for increased mitochondrial Ca2+ is the production of ROS, which has been demonstrated to follow NMDA stimulation [156], in a manner sensitive to removal of Ca2+ [157]. However, the interpretation of studies reporting measurements of ROS production is problematic, because the acute, real-time detection of free radicals (mainly through the use of fluorescent dyes) is notoriously difficult because of (1) the selectivity of various dyes for different ROS species, (2) the different sites at which the ROS are produced and their lifetime, and (3) the fact that the fluorescence of the dyes could be influenced by other enzymatic and non-enzymatic processes [158]. In addition, the bioenergetic process that leads from increased matrix Ca2+ to increased free radicals is not well established. Electron leak, generating free radicals, occurs predominantly within complex III in the respiratory chain, during the so-called “Q cycle,” although complex I can also participate in the ROS generation process [159]. The crucial feature of this process is that it requires high mitochondrial membrane potential [160], and thus the Ca2+ uptake should inhibit rather than evoke an increase of ROS. One proposed explanation invokes (1) the stimulatory effect of Ca2+ on the citric acid cycle, mentioned above and that should accelerate the electron transfer rate; and (2) an effect of Ca2+ on nitric oxide (NO) generation, which in turn would inhibit the activity at the complex IV in the respiratory chain creating further favorable conditions for electron leak at complex III [161]. However, with respect to the effect of the respiration rate on the generation of ROS, a point of subtlety was made in a recent review by Nicholls [162]. The cytosolic environment is well hypoxic with respect to the values of the partial pressure of oxygen in the circulation or in the tissues, due to the increased diffusion pat, but even in these conditions oxygen, as a substrate for the final four-electron reduction to water, is in excess, and in sufficient supply. Under these conditions, the single electron reduction that generates free radicals is not simply a proportional slippage of the main electron carrier path, but rather the contrary. The generation of free radicals is inversely proportional to the rate of respiration, such that the higher the respiration rate and the lower the membrane potential, the less time will the electrons spend at the sites of leakage [162].
Structure-activity relationships of Toxoplasma gondii cytochrome bc 1 inhibitors
Published in Expert Opinion on Drug Discovery, 2022
P. Holland Alday, Aaron Nilsen, J. Stone Doggett
Cytochromes are heme-containing enzymes that transfer electrons by virtue of the reversible oxidation state of Fe (II) and Fe (III) contained within the porphyrin ring of heme. Other heme-containing enzymes, such as cytochrome P450s involved in the biosynthesis of membrane sterols, are important drug targets for triazole antifungals and have also been evaluated in kinetoplastid parasites. However, the enzymatic activity and inhibitors of cytochromes involved in electron transfer compared to cytochrome P450s are highly distinct. The cyt bc1 complex contributes to the mitochondrial electrochemical gradient through a series of reactions collectively referred to as the Q cycle in which two molecules of ubiquinol are oxidized at the Qo (quinol oxidation) site and one molecule of ubiquinone (figure 1) is reduced at the Qi (quinone reduction) site. As a result, the Q cycle couples the oxidation of ubiquinol to the active transport of protons across the inner mitochondrial membrane, the regeneration of ubiquinone for other mitochondrial enzymes, and the reduction of the soluble electron carrier cyt c, which in turn reduces complex IV (Figure 2).
Gold nanoparticles potentiates N-acetylcysteine effects on neurochemicals alterations in rats after polymicrobial sepsis
Published in Journal of Drug Targeting, 2020
Fabricia Petronilho, Leonardo Tenfen, Amanda Della Giustina, Larissa Joaquim, Michele Novochadlo, Aloir Neri de Oliveira Junior, Erick Bagio, Mariana Pereira de Souza Goldim, Raquel Jaconi de Carli, Sandra Regina Santana de Aguiar Bonfante, Kiuanne Lino Lobo Metzker, Samara Muttini, Thayná Marinho dos Santos, Mariana Pacheco de Oliveira, Nicole Alessandra Engel, Gislaine Tezza Rezin, Luiz Alberto Kanis, Tatiana Barichello
Oxidative stress can impair mitochondrial function by inducing structural changes with subsequent loss of activity of a number of mitochondrial enzymes, compromising ATP synthesis [46]. In addition, the direct action of ROS in mitochondrial membrane lipids and proteins may result in the activation of apoptotic cascades [47]. On the other hand, mitochondria are also major sources of ROS in the intracellular space [48]. It is known that the efficiency of mitochondrial oxidative phosphorylation is compromised in sepsis, to some extent, secondary to mitochondrial membrane damage and impaired cytochrome complex function [49,50]. Consequently, electrons that would normally flow through the electron transport chain are diverted to the Q-cycle, generating superoxide [50]. Here, we showed that complex I activity decreased later after sepsis induction in the hippocampus and it was restored by AuNP and AuNP + NAC treatments.
Alterations in cerebral and cardiac mitochondrial function in a porcine model of acute carbon monoxide poisoning
Published in Clinical Toxicology, 2021
David H. Jang, Sarah Piel, John C. Greenwood, Matthew Kelly, Vanessa M. Mazandi, Abhay Ranganathan, Yuxi Lin, Jonathan Starr, Thomas Hallowell, Frances S. Shofer, Wesley B. Baker, Alec Lafontant, Kristen Andersen, Johannes K. Ehinger, Todd J. Kilbaugh
We performed a comprehensive analysis of mitochondrial respiration and ROS generation in cortical, hippocampal and cardiac apical tissue that consistently showed CIV dysfunction (with exception of cortical tissue) even at the low dose of CO utilized in our study [7]. While CO has multiple mechanisms of action that includes hypoxia, lipid peroxidation and inflammation, its effect on mitochondrial function is less clear [26]. Our prior studies have strongly implicated the effects of CO on cellular respiration, particular at CIV with resultant cellular dysfunction [8]. In this study, there were no overt signs of clinical toxicity (with the exception of tachycardia) such as lactate generation (a marker of global cellular hypoxia) or hypotension. However, there were clear signs of mitochondrial involvement indicating early cellular injury. In addition to the cortex, we also evaluated the effects of CO on hippocampal tissue. The hippocampus is in the region of the brain that is associated primarily with memory and the regulation of emotional responses. The hippocampus is sensitive to ischemia and is commonly injured in CO poisoning leading to DNS [27,28]. Even with the low dose CO exposure we used, there was clear involvement of the hippocampal region despite no significant effects in the cortical region of the brain. We also observed the same finding of CIV inhibition in cardiac tissue similar to what was observed in the hippocampal area of the brain. Despite the lack of overt cardiac toxicity manifesting as hypotension with the exception of tachycardia, this provides further support that early cellular changes may proceed clinical manifestation with either higher CO doses or duration [29]. We also obtained simultaneous measurement of ROS as combined hydrogen peroxide and superoxide using the AmR assay used in our previous works. Consistent with our findings of CIV inhibition with hippocampal and cardiac tissue we investigated; we found a significant increase in ROS in all tissue types at the 200-ppm dose we used. The main source of H2O2 production by mitochondria is at CIII, regulated specifically by single electron production of superoxide in the Q cycle [30]. The rate of superoxide production is enhanced by slowing the terminal transfer rate of electrons to molecular O2 by CO binding at CIV which may be the case in our study.