Reverse electron transfer in mitochondrial complex II (CII) plays an important role in hypoxia/anoxia, in particular, in ischemia, when the blood supply to an organ is disrupted and oxygen is not ...available. A computational model of CII was developed in this work to facilitate the quantitative analysis of the kinetics of quinol-fumarate reduction as well as ROS production during reverse electron transfer in CII. The model consists of 20 ordinary differential equations and 7 moiety conservation equations. The parameter values were determined at which the kinetics of electron transfer in CII in both forward and reverse directions would be explained simultaneously. The possibility of the existence of the "tunnel diode" behavior in the reverse electron transfer in CII, where the driving force is QH
, was tested. It was found that any high concentrations of QH
and fumarate are insufficient for the appearance of a tunnel effect. The results of computer modeling show that the maximum rate of succinate production cannot provide a high concentration of succinate in ischemia. Furthermore, computational modeling results predict a very low rate of ROS production, about 50 pmol/min/mg mitochondrial protein, which is considerably less than 1000 pmol/min/mg protein observed in CII in forward direction.
Succinate dehydrogenase (SDH) plays an important role in reverse electron transfer during hypoxia/anoxia, in particular, in ischemia, when blood supply to an organ is disrupted, and oxygen is not ...available. It was detected in the voltammetry studies about three decades ago that the SDHA/SDHB subcomplex of SDH can have such a strong nonlinear property as a "tunnel-diode" behavior in reverse quinol-fumarate reductase direction. The molecular and kinetic mechanisms of this phenomenon, that is, a strong drop in the rate of fumarate reduction as the driving force is increased, are still unclear. In order to account for this property of SDH, we developed and analyzed a mechanistic computational model of reverse electron transfer in the SDHA/SDHB subcomplex of SDH. It was shown that a decrease in the rate of succinate release from the active center during fumarate reduction quantitatively explains the experimentally observed tunnel-diode behavior in SDH and threshold values of the electrode potential of about -80 mV. Computational analysis of ROS production in the SDHA/SDHB subcomplex of SDH during reverse electron transfer predicts that the rate of ROS production decreases when the tunnel-diode behavior appears. These results predict a low rate of ROS production by the SDHA/SDHB subcomplex of SDH during ischemia.
The mitochondrial respiratory Complex II (CII) is one of key enzymes of cell energy metabolism, linking the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). CII reversibly ...oxidizes succinate to fumarate in the TCA cycle and transfers the electrons, produced by this reaction to the membrane quinone pool, providing ubiquinol QH2 to ETC. CII is also known as a generator of reactive oxygen species (ROS).
It was shown experimentally that succinate can serve as not only a substrate in the forward succinate-quinone oxidoreductase (SQR) direction, but also an enzyme activator. Molecular and kinetic mechanisms of this property of CII are still unclear.
In order to account for activation of CII by succinate in the forward SQR direction, we developed and analyzed a computational mechanistic model of electron transfer and ROS formation in CII. It was found that re-binding of succinate to the unoccupied dicarboxylate binding site when FAD is reduced with subsequent oxidation of FADH2 creates a positive feedback loop in the succinate oxidation. The model predicts that this positive feedback can result in hysteresis and bistable switches in SQR activity and ROS production in CII. This requires that the rate constant of re-binding of succinate has to be higher than the rate constant of the initial succinate binding to the active center when FAD is oxidized.
Hysteresis and bistability in the SQR activity and ROS production in CII can play an important physiological role. In the presence of hysteresis with two stable branches with high and low SQR activity, high SQR activity is maintained even with a very strong drop in the succinate concentration, which may be necessary in the process of cell functioning in stressful situations. For the same reason, a high stationary rate of ROS production in CII can be maintained at low succinate concentrations.
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•Computational model of electron flows in the respiratory Complex II was developed.•The Complex II model predicts a positive feedback loop in the succinate oxidation.•Complex II can operate as a bistable switch between two alternative stable states.•ROS production in Complex II may have a hysteretic behaviour.
Reactive oxygen species (ROS) function as critical mediators in a broad range of cellular signaling processes. The mitochondrial electron transport chain is one of the major contributors to ROS ...formation in most cells. Increasing evidence indicates that the respiratory Complex II (CII) can be the predominant ROS generator under certain conditions. A computational, mechanistic model of electron transfer and ROS formation in CII was developed in the present study to facilitate quantitative analysis of mitochondrial ROS production. The model was calibrated by fitting the computer simulated results to experimental data obtained on submitochondrial particles (SMP) prepared from bovine and rat heart mitochondria upon inhibition of the ubiquinone (Q)-binding site by atpenin A5 (AA5) and Complex III by myxothiazol, respectively. The model predicts that only reduced flavin adenine dinucleotide (FADH
2
) in the unoccupied dicarboxylate state and flavin semiquinone radical (FADH
•
) feature the experimentally observed bell-shaped dependence of the rate of ROS production on the succinate concentration upon inhibition of respiratory Complex III (CIII) or Q-binding site of CII, i.e., suppression of succinate-Q reductase (SQR) activity. The other redox centers of CII such as Fe-S clusters and Q-binding site have a hyperbolic dependence of ROS formation on the succinate concentration with very small maximal rate under any condition and cannot be considered as substantial ROS generators in CII. Computer simulation results show that CII disintegration (which results in dissociation of the hydrophilic SDHA/SDHB subunits from the inner membrane to the mitochondrial matrix) causes crucial changes in the kinetics of ROS production by CII that are qualitatively and quantitatively close to changes in the kinetics of ROS production by assembled CII upon inhibition of CIII or Q-binding site of CII. Thus, the main conclusions from the present computational modeling study are the following: (i) the impairment of the SQR activity of CII resulting from inhibition of CIII or Q-binding site of CII and (ii) CII disintegration causes a transition in the succinate-dependence of ROS production from a small-amplitude sigmoid (hyperbolic) shape, determined by Q-binding site or 3Fe-4S cluster to a high-amplitude bell-shaped kinetics with a shift to small subsaturated concentrations of succinate, determined by the flavin site.
Factors and mechanisms promoting resource-based radiation in animals still represent a main challenge to evolutionary biology. The modifications of phenotype tied with adaptive diversification may ...result from an environmentally related shift having occurred at the early stage of development. Here, we study the role of temperature dynamics on the reproductive sites in the early-life divergence and adaptive radiation of the salmonid fish Salvelinus malma dwelling in the Lake Kronotskoe basin (North-East Asia). Local sympatric charr ecomorphs demonstrate strict homing behaviour guiding the preordained distribution along tributaries and, hence, further development under different temperatures. We thoroughly assessed the annual temperature dynamics at the spawning grounds of each morph as compared to an ancestral anadromous morph. Then we carried out an experimental rearing of both under naturally diverging and uniformed temperatures. To compare the morphs' development under the dynamically changing temperatures, we have designed a method based on calculating the accumulated heat by the Arrhenius equation. The proposed equation shows a strong predictive power and, at the same time, is not bias-susceptible when the developmental temperature approximates 0°C. The temperature was found to significantly affect the charrs' early ontogeny, which underlies the divergence of developmental and growth rates between the morphs, as well as morph-specific ontogenetic adaptations to the spawning site's temperatures. As opposed to the endemic morphs from Lake Kronotskoe, the anadromous S. malma, being unexposed to selection оn highly specific reproduction conditions, showed a wide temperature tolerance, Our findings demonstrate that the hatch, onset timing of external feeding, and size dissimilarities between the sympatric morphs reveal themselves during the development under contrast temperatures. As a result of the observed developmental disparities, the morphs occupy specific definitive foraging niches in the lake.
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The main goal of this work was a quantitative analysis of the kinetics of the formation of reactive oxygen species (ROS) by complex II of the mitochondrial respiratory chain. For this purpose, a ...mathematical model was developed for modeling and experimental studies of changes in mitochondria associated with ROS-induced activation of signaling pathways of cell death (apoptosis, necrosis, and necroptosis). A kinetic scheme of electron transfer from succinate to coenzyme Q through a number of redox centers localized in subcomplexes A, B, C, and D of complex II was developed on the basis of published experimental data. The mathematical model corresponding to the kinetic scheme is a system of 17 ordinary differential equations that describes both the concentration of oxidized and reduced states of various electron carriers and the electron flows in complex II, leading to the formation of ROS, superoxide (
) and hydroperoxide (H
2
O
2
). The results of analysis of the mathematical model have shown that the bell-shaped kinetics of the ROS formation observed experimentally at a micromolar range of succinate concentrations (from tens to hundreds micromoles of succinate) in the presence of the inhibitors of complex III was an inherent property of only flavin adenine dinucleotide (FADH2) and flavin adenine dinucleotide radical (FADH
∙
), two potential generators of ROS. At the same time, ROS formation by the Fe–S redox centers of complex II, as well as ubiquinone-binding center exhibited about sigmoidal kinetics; apparently, these redox centers make a minor contribution to the overall production of ROS by complex II upon the inhibition of complex III.
The pygmy whitefish Prosopium coulterii (C. H. Eigenmann & R. S. Eigenmann, 1892) is a freshwater fish with a highly disjunct distribution ranging from the middle part of North America to Chukotka. ...There is still no consensus regarding its phylogeny and dispersal history due to limited information from the Chukotkan part of the range. We investigated 22 lakes over Chukotka and found a much broader distribution than it was previously thought. Pygmy whitefish was found to be a common species in the lakes that belong to rivers draining into the Arctic. Cytochrome B, cytochrome oxidase subunit 1, and ATP synthase F0 subunit 6 mitochondrial sites were analyzed from 25 samples to reconstruct the phylogenetic history of pygmy whitefish. Two haplogroups belonging to the east and west Chukotkan ranges were identified; both groups are closely related to Alaskan pigmy whitefish and distant from the Cascadia-Mackenzie (Peace) populations. Combining the distribution patterns, phylogenetic network topology, and the contemporary knowledge on the glaciation history of the region, we suggest a possible colonization pathway over Beringia region and beyond it. The basic biological characteristics (fork length, number of gill rakers, and pyloric caeca, age structure, and feeding) are also presented to characterize the populations over the investigated range.
In the present study, we estimated the levels of infestation of the main fish species that are hosts for two Triaenophorus species: T. crassus and T. nodulosus. The prevalence of T. crassus and T. ...nodulosus infestations in the intestine of their definitive host–pike Esox lucius was similar (71.0% and 77.4%, respectively). At the same time, the prevalence of T. crassus infestation in muscle tissue was significantly different between the second intermediate hosts, Coregonus lavaretus pidschian (31.4%) and Cor. l. pravdinellus (91.2%), due to considerable differences in their diets. For T. nodulosus, we found significant variations in the levels of prevalence among the second intermediate hosts—100% for Lota lota, 81.8% for Cottus sibiricus 31.9% for Thymallus arcticus, and 24.5% for Perca fluviatilis—that we also explained using different diets. Moreover, analysis of the symmetry of parasite infestations did not reveal any asymmetry between the number of cysts in the left and right body surfaces of the “planktivorous” form/species of whitefish, whereas in the ‘‘benthivorous”, an asymmetry of parasite infestations was found.
Within the sympatric evolution framework a range of ecological variables are considered as potential initiators and controllers of the diversification process. Here, we identify the proximate factors ...providing the reproductive isolation among seven sympatric ecomorphs of the genus
Salvelinus
charr dwelling in the Lake Kronotskoe basin (North-East Asia). We demonstrate that the slope profile of the lake tributaries determining the water flow velocity and position of the groundwater discharges serves as a barrier between the reproductive sites of the ecomorphs and provides the basis for selective pressure affecting the Lake Kronotskoe fish during spawning. The main characteristic under selection is a migratory ability, which is determined by the swimming performance and the amount of energy reserved in the body and depends on fish morphology and physiology. The flex points indicating abrupt slope changes along the spawning watercourse restrict the upstream migration of the groups having a comparatively low swimming performance and energy reserve. A thorough analysis of the ecomorphs’ migratory and spawning activity indicated two energy expenditure strategies: the fish could invest most of the energy either on migration or spawning. Our findings supported with data on fish ecology, morphology, and thyroid hormone status allow us to put forward a following hypothesis. We suggest that the interplay of spatially heterogeneous environmental variables affecting life history decisions via ecomorphological and physiological traits could serve as a trigger for the reproductive isolation among the ecomorphs in a single ecosystem.
Sympatric fish morphs diversifying in their feeding pattern in fresh waters typically implement alternative migratory tactics so that omnivores become migrants and specialists‐residents. Charrs of ...the genus Salvelinus populating the lower Kamchatka River (Northeast Asia) are a rare example wherein two related sympatric morphs both implement a variety of life‐history tactics in parallel. Here the authors analyse the ecological diversity in the endemic piscivorous “white” morph that exploits resources of the Kamchatka River in sympatry with the partially anadromous invertivorous “Dolly Varden” (DV) morph. Eco‐morphological criteria allowed the authors to validate the morph identification. The white charr (WC) was found to subdivide into the small‐sized (up to 1.6 kg) fish inhabiting the lacustrine part of the ecosystem and the large‐sized (up to 3.4 kg) fish inhabiting the main river channel. The persistent spatial segregation of the sub‐groups was confirmed by significant differences in the life span, muscle δ13С signature and parasite load. According to contrasting patterns of strontium accumulation in otoliths, the riverine WC is represented by resident and semi‐anadromous individuals. At the same time, the lack of microsatellite DNA differentiation and allometric nature of the morphometric discrepancy point to the intra‐population source of the WC polymorphism. The authors suggest that WC diverged from DV as a result of feeding specialization on the threespine stickleback numerous in the ecosystem since the temporary flooding by marine waters in the middle Holocene. The modern stickleback division into local stocks following the ecosystem differentiation into a river, side lake and estuary resulted in the WC life‐history split and ecological radiation.
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