Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology最新文献

Mesenchymal stromal cells (MSCs) are universal regulators of regenerative processes due to their ability to paracrine release of regulatory molecules or to replace dead cells by differentiation in the appropriate direction. Recently, another mechanism for the beneficial effects of MSCs on damaged tissues has been discovered, namely transfer of mitochondria into its cells in response to stress signals. MSCs can transfer mitochondria through tunnel nanotubes forming a connecting bridge between cells, through gap junctions, by release as part of extracellular vesicles or in the free form, as well as by complete or partial fusion with recipient cells. In the damaged cells that received mitochondria from MSCs, the disturbed energy metabolism is restored and oxidative stress is reduced, which is accompanied by increased survival, and in some cases also by increased proliferation or changes in differentiation status. Restoration of energetics after mitochondria transfer from MSCs has a beneficial effect on functional activity of recipient cells and promotes suppression of inflammatory reactions. It has been repeatedly demonstrated on models of damage of various organs in experimental animals that the transfer of mitochondria from MSCs to target cells makes a significant contribution to the therapeutic efficacy of MSCs. Therefore, methods to enhance mitochondrial donation are currently being searched for. However, it should be taken into account that MSCs are able to transfer mitochondria to malignant cells, thus stimulating tumor growth and increasing its resistance to chemotherapy. These data make us cautious about the prospects of using MSCs in cell therapy, but, on the other hand, they can serve as a basis for searching for new therapeutic targets in the treatment of cancer.

Various RNAs are among the most promising and actively developed therapeutic agents for the treatment of tumors, infectious diseases and a number of other pathologies associated with the dysfunction of specific genes. Some nanocarriers are used for the effective delivery of RNAs to target cells, including liposomes based on cationic and/or ionizable amphiphiles. Cationic amphiphiles contain a protonated amino group and exist as salts in an aqueous environment. Ionizable amphiphiles are a new generation of cationic lipids that exhibit reduced toxicity and immunogenicity and undergo ionization only in the acidic environment of the cell. In this work we developed a scheme for the preparation and carried out the synthesis of new cationic and ionizable amphiphiles based on natural amino acids (L-glutamic acid, glycine, β-alanine, and γ-aminobutyric acid). Cationic and ionizable liposomes were formed based on the obtained compounds, mixed with natural lipids (phosphatidylcholine and cholesterol), and their physicochemical characteristics (particle size, zeta potential, and storage stability) were determined. Average diameter of particles stable for 5–7 days did not exceed 100 nm. Zeta potential of cationic and ionizable liposomes was about 30 and 1 mV, respectively. The liposomal particles were used to form complexes with RNA molecules. Such RNA complexes were characterized by atomic force microscopy and their applicability for nucleic acid transport was determined.

OTOP1 belongs to the otopetrin family of membrane proteins that form proton channels in cells of diverse types. In mammals, OTOP1 is involved in sour transduction in taste cells and contributes to otoconia formation in the inner ear. From the structural point of view, otopetrins, including OTOP1, represent a quasi-tetramer consisting of four α-barrels. The exact transport pathways mediating proton flux through the OTOP1 channel and gating elements modulating its activity are still a matter of debate. This review discusses current data on structural and functional features of OTOP1. Suggested proton transport pathways, regulatory mechanisms, and key amino acid residues determining functionality of the otopetrins are considered. The existing kinetic models of OTOP1 are discussed. Based on revealed functional properties, OTOP1 is suggested to operate as a logical XOR element that allows for proton flux only if transmembrane pH gradient exists.

The superfamily of membrane proteins known as P-loop channels encompasses potassium, sodium, and calcium channels, as well as TRP channels and ionotropic glutamate receptors. An increasing number of crystal and cryo-EM structures are uncovering both general and specific features of these channels. Fundamental folding principles, the arrangement of structural segments, key residues that influence ionic selectivity, gating, and binding sites for toxins and medically relevant ligands have now been firmly established. The advent of AlphaFold2 models represents another significant step in computationally predicting protein structures. Comparison of experimental P-loop channel structures with their corresponding AlphaFold2 models shows consistent folding patterns in experimentally resolved regions. Despite this remarkable progress, many crucial structural details, particularly important for predicting the outcomes of mutations and designing new medically relevant ligands, remain unresolved. Certain methodological challenges currently hinder the direct assessment of such details. Until the next methodological breakthrough occurs, a promising approach to analyzing ion channel structures in greater depth involves integrating various experimental and theoretical methods.

The review presents the history of the origin, development, and achievements of the Rhodopsin Project organized by Yu.A. Ovchinnikov in 1973. The current state of some issues related to the structure and function of retinal-containing proteins, rhodopsin types I and II, is also considered.

Membranes of living cells, or biological membranes, are unique molecular systems in which the functioning of all molecules is interdependent and coordinated, and disruption of this coordination can be fatal for the cell. One example of such coordination and mutual regulation is the functioning of membrane proteins, whose activity depends on their interaction with membrane lipids. This review summarizes the facts about the importance of the cholesterol component of cell membranes for the normal functioning of membrane proteins and the whole cell. This lipid component provides fine regulation of a variety of cellular functions and provides clues to understanding changes in the activity of a number of proteins under various physiologic and pathologic conditions. This review provides examples of cholesterol-dependent membrane proteins and cellular processes and discusses their role in several pathologies. Understanding the mechanisms of cholesterol–protein interactions represents a significant resource for the development of drugs that affect the cholesterol–protein interface.

Illuminated giant cells of Characeae produce alternating areas with H⁺-pump activity and zones of high H⁺/OH^– conductance, where H⁺ fluxes between the medium and the cytoplasm are oppositely directed. In areas where proton equivalents enter the cell, the pH on cell surface (pH_o) increases to pH 10, while the cytoplasmic pH (pH_c) decreases. Deficiency of the permeant substrate of photosynthesis (CO₂) and the acidic pH_c shift under external alkaline zones promote the redirection of electron transport in chloroplasts from CO₂-dependent assimilatory pathway to O₂ reduction. This bypass route of electron transport elevates the thylakoid membrane ΔpH and enhances nonphotochemical quenching (NPQ) of chlorophyll excitations, which determines strict coordination between nonuniform distributions of pH_o and photosynthetic activity in resting cells. When the action potential (AP) is generated, the longitudinal pH profile is temporarily smoothed out, while the heterogeneous distribution of NPQ and PSII photochemical activity (YII) becomes drastically sharpened. The damping of the pH_o profile is due to the suppression of the H⁺-pump and passive H⁺/OH^– conductance under the influence of an almost 100-fold increase in the cytoplasmic Ca²⁺ level ([Ca²⁺]_c) during AP. The increase in [Ca²⁺]_c stimulates photoreduction of O₂ in chloroplasts underlying external alkaline zones and, at the same time, arrests the cytoplasmic streaming, which lead to the accumulation of excess amounts of H₂O₂ in the cytoplasm in areas of intense production of this metabolite and has a weak effect on areas of CO₂ assimilation. These changes enhance the nonuniform distribution of cell photosynthesis and account for long-term oscillations of chlorophyll fluorescence (F_{{text{m}}}^{{{'}}}) and the quantum efficiency of linear electron flow on microscopic cell areas after the AP generation.

Sterol biosynthesis has evolved early in the history of eukaryotes. In most animals, as well as in primitive fungi, the main sterol is cholesterol. During the process of evolution, fungi acquired the ability to synthesize ergosterol. The pathway of its biosynthesis is more complex than the one of cholesterol biosynthesis. However, the evolutionary choice of most fungi was ergosterol, and the reason for this choice is still debated. In the majority of the works on this issue, the choice of most fungi is associated with the transition to life on land, and, consequently, the danger of cell dehydration. In our review we oppose this point of view. Probably, compared to cholesterol, ergosterol has more pronounced antioxidant properties. Indeed, the presence of three double bonds in the structure of the ergostеrol molecule, as compared to one in cholesterol, increases the probability of interaction with reactive oxygen species. Perhaps, the transition to life on land required additional antioxidant protection. Due to the aforementioned structural differences, the molecule of cholesterol is apparently more flexible than that of ergosterol. Experimental data indicate that this feature provides greater membrane flexibility as compared to fungal membranes, as well as a greater ability to compensate for disturbances in the packing of membrane phospholipids. Presumably, for animal cells these qualities turned out to be relatively more important than antioxidant ones, which predetermined their evolutionary choice of sterol.

Neurodegenerative diseases, along with cardiovascular and oncological pathologies, are one of the most acute problems of modern medicine requiring an integrated approach to the study of the molecular mechanisms of their pathogenesis and the search for new targets for the drug treatment. Neuronal calcium signaling deserves close attention of researchers; numerous violations of it have been noted in the study of a number of neurodegenerative pathologies. In this review, we have focused on one of the most common and important ways of calcium influx into the cell, store-operated calcium entry. Here are collected studies demonstrating alterations of the store-operated calcium entry in various neurodegenerative diseases, primarily in Alzheimer’s, Parkinson’s, and Huntington’s diseases, the molecular determinants mediating these disorders are analyzed, and ways of their pharmacological correction are proposed. The information summarized in this review will allow us to look at store-operated channels as one of the most promising targets in the search for new therapeutic agents to treat neurodegenerative pathologies and outline further promising directions of research in this area.

The complex mechanism called hemostasis evolved in living organisms to prevent blood loss when a blood vessel is damaged. In this process, two closely interconnected systems are distinguished: platelet-vascular and plasmatic hemostasis. Plasmatic hemostasis is a system of proteolytic reactions, in which blood plasma proteins called coagulation factors are involved. A key feature of this system is the localization of enzymatic reactions on the surface of phospholipid membranes, which increases their rate by up to 5 orders of magnitude. This review describes the basic mechanisms of coagulation factors binding to phospholipid membranes, the pathways for complex assembly and activation reactions, and discusses the role of membranes in this process, their composition and sources. The binding of coagulation factors to procoagulant membranes leads not only to the acceleration of coagulation reactions, but also to their selective localization in restricted areas and protection from being washed away by the flow. The efficiency of coagulation reactions is regulated by the composition of the outer layer of the membrane, primarily through a special mechanism of mitochondria-dependent necrotic platelet death.