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Mitochondrial Dysfunction in Chronic Disease
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Christopher Newell, Heather Leduc-Pessah, Aneal Khan, Jane Shearer
Acting as a tight barrier to all ions and molecules from the matrix and intermembrane space, the IMM utilizes a proton gradient to drive ATP synthesis. Embedded in the IMM are a series of large enzyme complexes, which generate this proton gradient, collectively termed the electron transport system (ETS) (Figure 26.1). Once liberated from metabolic substrates, electrons are shuttled through the ETS via NADH dehydrogenase (Complex I) or succinate dehydrogenase (SDH; Complex II). Electrons are then carried by the mobile electron carrier ubiquinone (coenzyme Q or CoQ) to cytochrome c reductase (Complex III) before being transferred to cytochrome c, with cytochrome c oxidase (COX; Complex IV) eventually receiving the electrons. Complex IV enables O2 to accumulate four electrons, which generates one molecule of H2O. The drop in free energy that occurs drives proton pumping at Complexes I, III, and IV from the matrix into the mitochondrial intermembrane space. Complex II only transfers electrons to coenzyme Q and does not help generate the proton gradient. The proton redistribution established by mitochondrial respiration maintains and modulates the IMM proton gradient, which drives the formation of ATP via mitochondrial ATP synthase (Complex V). Interestingly, the organization of mitochondrial cristae is tightly linked to the location of ETS enzyme complexes embedded in the IMM (64).
Role of Ascorbate and Dehydroascorbic Acid in Metabolic Integration of the Cell
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Gábor Bánhegyi, András Szarka, József Mandl
To clarify these questions around mitochondrial vitamin C transport, an enriched hydroxyapatite fraction from highly purified rat liver and potato mitochondria was reconstituted in proteoliposomes, and a functional ascorbic acid transporter was found in them [70]. Two main protein bands in the range of 28–35 kDa were found both in rat and potato hydroxyapatite eluates. The presence of SVCT2 or GLUTs was excluded, since they can be characterized by higher molecular masses ranges between 55 and 60 kDa. The protein showed unidirectional transport and could be stimulated by the generation of an inwardly directed proton gradient. In contrast to GLUT1 and SVCT2, which has a pH optimum at pH 7.5–8 [28,83], it has a pH optimum between 6.5 and 7 [70]. The rat and potato proteins showed similar inhibitor sensitivity, and both were highly sensitive to only the lysine blocking reagent pyridoxal phosphate, while neither of them was affected by typical SVCT2 or GLUT inhibitors. Contrary to the ascorbate uptake mediated by SVCTs, ascorbate uptake into proteoliposomes, reconstituted with both potato and rat liver mitochondrial extract, was not influenced by the presence of sodium and can be characterized by much higher KM (8.4–60 μM versus 1.5 mM) [11,28].
Structure, Function and Evolutionary Aspects of Mitochondria
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Puja Agarwal, Mehali Mitra, Sujit Roy
Uncouplers such as DNP (2,4-dinitrophenol), paratrifluromethoxy hydrazone etc prevent synthesis of ATP without interfering in electron transport to proceed smoothly (Formentini et al., 2012). but this flow cannot be coupled to ATP synthesis. DNP and para-trifluromethoxy hydrazone are lipophilic in nature and can easily pass through the cytoplasmic membrane (Garlid et al., 2000). They are also acidic in nature and can bind with proton to carry inside from outside of the membrane; thus they prevent generation of the proton gradient.
Design of α-helical antimicrobial peptides with a high selectivity index
Published in Expert Opinion on Drug Discovery, 2019
In this review, we shall mostly consider cationic linear AMPs with high selectivity and activity having at least one known or predicted amphipathic helical segment. Some natural lytic proteins, longer peptides, and bacteriocins are known to be top achievers with respect to their antibacterial activity and selectivity, but our favorites in this review will be peptides with less than 50 amino acid residues and proteinogenic amino acid residues. The focus will be on simple methods with which nature’s design can be improved by using expert knowledge, computer-guided design, and user-friendly web servers. Magainin-2 and its pexiganan (MSI-78) analogue [2] have been abundantly examined during the past 30 years [3]. They are convenient yardsticks for judging design success for other helical AMPs, either by natural evolution or by rational design. Most short AMPs, like magainins, have a random structure in an aqueous solution but are induced by bacterial-like anionic membranes to assume partially helical amphipathic conformation suitable for dynamic membrane pore formation. Subsequent short-circuits of proton transport cannot be tolerated by bacteria, which is highly dependent on creating and maintaining proton-motive force through a proton gradient and a very strong electric field. Intracellular targets for some cationic AMPs with antibiotic activity also require membrane-active peptides with the ability to interact with and pass through the cytoplasmic membrane.
The Warburg hypothesis and weak ELF biointeractions
Published in Electromagnetic Biology and Medicine, 2020
It has long been known (Warburg et al. 1924) that the energy currency for cancer cells is obtained from a different source than normal cells. As a rule ATP is generated by the proton gradient across the inner mitochondrial membrane, making convenient use of the rotating enzyme ATP Synthase (ATPS) (Boyer 1997) embedded within this membrane. The ATP Synthase enzyme consists of two connected parts: F0 embedded in the inner mitochondrial membrane, and F1, located within the mitochondrial interior. Warburg observed that cancer cells bypass the ATPS step, instead merely using the oxidation of glucose (glycolysis) to provide its ATP. This is counterintuitive because in so doing cancer cells fail to make use of the more highly efficient ATP Synthase mechanism.
High extracellular phosphate increases platelet polyphosphate content
Published in Platelets, 2021
Nima Abbasian, Matthew T. Harper
How PolyP is synthesized and regulated in mammalian cells is not well understood. In fungi and some protists, such as Trypanosoma and Leishmania, PolyP synthesis requires a vacuolar transporter chaperone complex. PolyP that is synthesized at the cytoplasmic face of acidocalcisome-like organelles by this complex is translocated into the organelle lumen. A transmembrane proton gradient generated by V-type ATPase activity is also required[15]. Notably, platelet polyphosphate is stored in dense granules, a secretory lysosome-like organelle that has an acidic lumen and is similar to acidocalcisomes[4]. Since bafilomycin prevented the increase in PolyP, platelets may use the proton gradient across the dense granule membrane to synthesize and accumulate PolyP.