Autocatalytic cycle in the pathogenesis of diabetes mellitus: biochemical and pathophysiological aspects of metabolic therapy with natural amino acids on the example of glycine

In this work systematization (classification) of biochemical and physiological processes that cause disorders in the human body during the development of diabetes mellitus is carried out. The development of the disease is considered as the interaction and mutual reinforcement of two groups of parallel processes. The first group has a molecular nature and it is associated with impairment of ROS-regulation system which includes NADPH oxidases, RAGE receptors, mitochondria, cellular peroxireductase system and the immune system. The second group has a pathophysiological nature and it is associated with impairment of microcirculation and liver metabolism. The analysis of diabetes biochemistry based on different published references yields a creation of a block diagram evaluating the disease development over time. Two types of autocatalytic processes were identified: autocatalysis in the cascade of biochemical reactions and "cross-section" catalysis, in which biochemical and pathophysiological processes reinforce each other. The developed model has shown the possibility of using pharmacologically active natural metabolite glycine as a medicine inhibiting the development of diabetes. Despite the fact that glycine is a substitute amino acid the drop in the glycine blood concentration occurs even in the early stages of diabetes development and can aggravate the disease. It is shown that glycine is a potential blocker of key autocatalytic cycles, including biochemical and pathophysiological processes. The analysis of the glycine action based on the developed model is in complete agreement with the results of clinical trials in which glycine has improved blood biochemistry of diabetic patients and thereby it prevents the development of diabetic complications

Ordered Clusters of the Complete Oxidative Phosphorylation System in Cardiac Mitochondria

The existence of a complete oxidative phosphorylation system (OXPHOS) supercomplex including both electron transport system and ATP synthases has long been assumed based on functional evidence. However, no structural confirmation of the docking between ATP synthase and proton pumps has been obtained. In this study, cryo-electron tomography was used to reveal the supramolecular architecture of the rat heart mitochondria cristae during ATP synthesis. Respirasome and ATP synthase structure in situ were determined using subtomogram averaging. The obtained reconstructions of the inner mitochondrial membrane demonstrated that rows of respiratory chain supercomplexes can dock with rows of ATP synthases forming oligomeric ordered clusters. These ordered clusters indicate a new type of OXPHOS structural organization. It should ensure the quickness, efficiency, and damage resistance of OXPHOS, providing a direct proton transfer from pumps to ATP synthase along the lateral pH gradient without energy dissipation

Contribution of the Collective Excitations to the Coupled Proton and Energy Transport along Mitochondrial Cristae Membrane in Oxidative Phosphorylation System

The results of many experimental and theoretical works indicate that after transport of protons across the mitochondrial inner membrane (MIM) in the oxidative phosphorylation (OXPHOS) system, they are retained on the membrane–water interface in nonequilibrium state with free energy excess due to low proton surface-to-bulk release. This well-established phenomenon suggests that proton trapping on the membrane interface ensures vectorial lateral transport of protons from proton pumps to ATP synthases (proton acceptors). Despite the key role of the proton transport in bioenergetics, the molecular mechanism of proton transfer in the OXPHOS system is not yet completely established. Here, we developed a dynamics model of long-range transport of energized protons along the MIM accompanied by collective excitation of localized waves propagating on the membrane surface. Our model is based on the new data on the macromolecular organization of the OXPHOS system showing the well-ordered structure of respirasomes and ATP synthases on the cristae membrane folds. We developed a two-component dynamics model of the proton transport considering two coupled subsystems: the ordered hydrogen bond (HB) chain of water molecules and lipid headgroups of MIM. We analytically obtained a two-component soliton solution in this model, which describes the motion of the proton kink, corresponding to successive proton hops in the HB chain, and coherent motion of a compression soliton in the chain of lipid headgroups. The local deformation in a soliton range facilitates proton jumps due to water molecules approaching each other in the HB chain. We suggested that the proton-conducting structures formed along the cristae membrane surface promote direct lateral proton transfer in the OXPHOS system. Collective excitations at the water–membrane interface in a form of two-component soliton ensure the coupled non-dissipative transport of charge carriers and elastic energy of MIM deformation to ATP synthases that may be utilized in ATP synthesis providing maximal efficiency in mitochondrial bioenergetics

Liquid-liquid Phase Separation as a Common Organizing Principle of Intracellular Space and Biomembranes Providing Dynamic Adaptive Responses

This work is devoted to the phenomenon of liquid-liquid phase separation (LLPS), which has come to be recognized as fundamental organizing principle of living cells. We distinguish separation processes with different dimensions. Well-known 3D-condensation occurs in aqueous solution and leads to membraneless organelle (MLOs) formation. 2D-films may be formed near membrane surfaces and lateral phase separation (membrane rafts) occurs within the membranes themselves. LLPS may also occur on 1D structures like DNA and the cyto- and nucleoskeleton. Phase separation provides efficient transport and sorting of proteins and metabolites, accelerates the assembly of metabolic and signaling complexes, and mediates stress responses. In this work, we propose a model in which the processes of polymerization (1D structures), phase separation in membranes (2D structures), and LLPS in the volume (3D structures) influence each other. Disordered proteins and whole condensates may provide membrane raft separation or polymerization of specific proteins. On the other hand, 1D and 2D structures with special composition or embedded IDRs can nucleate condensates. We hypothesized that environmental change may trigger a LLPS which can propagate within the cell interior moving along the cytoskeleton or as an autowave. New phase propagation quickly and using a low amount of energy adjusts cell signaling and metabolic systems to new demands. Cumulatively, the interconnected phase separation phenomena in different dimensions represent a previously unexplored system of intracellular communication and regulation which cannot be ignored when considering both physiological and pathological cell processes

Энергетический метод для эллиптических краевых задач с несимметричными операторами в шаровом слое

Three-dimensional elliptic boundary value problems arising in the mathematical modeling of quasi-stationary electric fields and currents in conductors with gyrotropic conductivity tensor in domains homeomorphic to the spherical layer are considered. The same problems are mathematical models of thermal conductivity or diffusion in moving or gyrotropic media. The operators of the problems in the traditional formulation are non-symmetric. New statements of the problems with symmetric positive definite operators are proposed. For the four boundary value problems the quadratic energy functionals, to the minimization of which the solutions of these problems are reduced, are constructed. Estimates of the obtained quadratic forms are made in comparison with the form appearing in the Dirichlet principle for the Poisson equationРассмотрены трехмерные эллиптические краевые задачи, возникающие при математическом моделировании квазистационарных электрических полей и токов в проводниках с гиротропным тензором проводимости в областях, гомеоморфных шаровому слою. Аналогичные задачи формулируются при моделировании теплопроводности или диффузии в движущихся или гиротропных средах. Операторы задач в традиционной формулировке является несимметричными. Предложены новые формулировки задач с симметричными положительно определенными операторами. Для четырех краевых задач построены квадратичные функционалы энергии, к минимизации которых сведено решение этих задач. Выполнены оценки полученных квадратичных форм в сравнении с формой, фигурирующей в принципе Дирихле для уравнения Пуассон

On the Role of Normal Aging Processes in the Onset and Pathogenesis of Diseases Associated with the Abnormal Accumulation of Protein Aggregates

Aging is a prime systemic cause of various age-related diseases, in particular, proteinopathies. In fact, most diseases associated with protein misfolding are sporadic, and their incidence increases with aging. This review examines the process of protein aggregate formation, the toxicity of such aggregates, the organization of cellular systems involved in proteostasis, and the impact of protein aggregates on important cellular processes leading to proteinopathies. We also analyze how manifestations of aging (mitochondrial dysfunction, dysfunction of signaling systems, changes in the genome and epigenome) facilitate pathogenesis of various proteinopathies either directly, by increasing the propensity of key proteins for aggregation, or indirectly, through dysregulation of stress responses. Such analysis might help in outlining approaches for treating proteinopathies and extending healthy longevity

Ionospheric Layer Variability Prior to Strong Earthquakes During Quiet Geomagnetic Conditions

International audienceWe report on electric field measurements recorded by the Electric Field Detector (EFD) and the Instrument Champ Electrique (ICE) onboard, respectively, CSES and DEMETER satellites. We study the variations of Very Low Frequency (VLF) ground-based transmitter signals detected by both satellites during periods of low solar and geomagnetic activities. We consider the variation of VLF power spectra density in the frequency range between few Hertz to 20 kHz. We emphasize on ionospheric disturbances associated to earthquakes occurrences. Such disturbances are linked to waves generated by coupling of neutral particles and electrons related, through the atmosphere, to lithospheric ground displacements. The main peculiarities of seismic ionospheric anomalies are summarized taken into consideration technical complementary of both satellites