Biochemistry (Moscow)最新文献

This article is a translation of the first chapter from the book “The Discovery of Magnetic Resonance in the Context of 20th Century Science: Biographies and Bibliography”. The book, dedicated to the 75th anniversary of magnetic resonance discovery, chronicles the history and bibliography of this major breakthrough in the 20th century physics (in Russian). In it, biographical accounts of E. K. Zavoisky, E. M. Purcell, and F. Bloch, outstanding physicists and fathers of magnetic resonance methods, are given. For each, a path to this discovery and works beyond it are described. Research preceding the discovery of the electron spin resonance and nuclear magnetic resonance as well as the first works in this new field of science are discussed.

In this chapter, we provide a bibliography of research in the field of ESR, NMR and related phenomena, such as magneto-mechanical resonance, a technique used both to detect magnetic resonance and to confirm magnetic flux quantization; along with exotic atom-related resonances, muon spin resonance and the fine structure and Zeeman effect of positronium. For the reference list provided in this book, out of dozens of thousands of studies we selected several hundred works which we believe represent major lines of research and development in the field of magnetic resonance. The list of literature is structured into several sections: I. Historiography (including reminiscences); II. Monographs, Overviews, and Subject Collections; III. Internet (reference material); IV. Original Research Papers. The latter is further broken down into several subsections covering the development of magnetic resonance foundational ideas (subsection IV.1.), studies on paramagnetic and ferromagnetic absorption and dispersion (IV.2.), works on molecular-beam and atomic-beam magnetic resonance (IV.3.), and original research papers on different magnetic resonances in condensed matter and on their applications (IV.4.). The reference list is provided with brief commentary.

Oxidative phosphorylation in mitochondria is the main source of ATP in most eukaryotic cells. Concentrations of ATP, ADP, and AMP affect numerous cellular processes, including macromolecule biosynthesis, cell division, motor protein activity, ion homeostasis, and metabolic regulation. Variations in ATP levels also influence concentration of free Mg²⁺, thereby extending the range of affected reactions. In the cytosol, adenine nucleotide concentrations are relatively constant and typically are around 5 mM ATP, 0.5 mM ADP, and 0.05 mM AMP. These concentrations are mutually constrained by adenylate kinases operating in the cytosol and intermembrane space and are further linked to mitochondrial ATP and ADP pools via the adenine nucleotide translocator. Quantitative data on absolute adenine nucleotide concentrations in the mitochondrial matrix are limited. Total adenine nucleotide concentration lies in the millimolar range, but the matrix ATP/ADP ratio is consistently lower than the cytosolic ratio. Estimates of nucleotide fractions show substantial variability (ATP 20-75%, ADP 20-70%, AMP 3-60%), depending on the organism and experimental conditions. These observations suggest that the ‘state 4’ – inhibition of oxidative phosphorylation in the resting cells due to the low matrix ADP and elevated proton motive force that impedes respiratory chain activity – is highly unlikely in vivo. In this review, we discuss proteins regulating ATP levels in mitochondria and cytosol, consider experimental estimates of adenine nucleotide concentrations across a range of biological systems, and examine the methods used for their quantification, with particular emphasis on the genetically encoded fluorescent ATP sensors such as ATeam, QUEEN, and MaLion.

The Mitochondrial Permeability Transition pore (MPT pore) activated by Ca²⁺ ions is a phenomenon that has long been the subject of intense study. Cyclophilin D-dependent opening of the MPT pore in mitochondria in response to calcium overload and oxidative stress leads to swelling of the mitochondrial matrix, depolarization of the inner membrane and dysregulation of ion homeostasis. These processes are accompanied by damage to mitochondrial membranes and, ultimately, to cell death. Despite decades of research, the molecular identity of the MPT pore remains unclear. Currently, the inner membrane proteins – ATP synthase and adenine nucleotide translocator (ANT) – are considered to be its key structural components, along with the regulatory protein cyclophilin D. The involvement of the MPT pore in the progression of various pathological conditions and diseases, as well as in a number of physiological processes, such as the regulation of cellular bioenergetics and rapid release of Ca²⁺, is widely discussed. This review summarizes modern molecular genetic data on the putative structure of the MPT pore, traces the evolution of views on its functioning – from interpreting it as a simple experimental artifact to its recognition as a putative key regulator of energy metabolism – and also considers the mechanisms of its regulation and its multifaceted pathophysiological role.

Antibiotics are certainly the most important agents in the fight against human and animal bacterial infections. Widespread use of antibiotics has a positive impact on the treatment of infectious diseases but may be accompanied by serious side effects. Clinical aspects of these side effects are well understood, but nonspecific molecular targets are not fully recognized. It is generally known that many antibiotics can damage mitochondria, intracellular organelles responsible for aerobic metabolism as well as regulating a number of important processes, including cellular redox balance and inflammatory responses. Mitochondrial dysfunction commonly leads to the development of oxidative stress and inflammation, which are known stimuli of cellular senescence. On the other hand, the same stimuli could induce death of senescent cells. Thus, mitotoxic antibiotics could influence both the cellular senescence process and elimination of senescent cells. The effect of antitumor antibiotics on the induction of cell aging has been studied in detail, but the effect of antibacterial antibiotics on this process is still essentially unknown. This review aims to draw attention of the researchers to the possibility of accelerated cellular aging induced by common antibacterial antibiotics and to discuss potential mechanisms of this process.

Maintenance of ionic homeostasis, particularly the balance of potassium ions as the major cations in the cytoplasm, is critically important for mitochondrial function. Uncontrolled cation influx and the subsequent osmotically-driven water accumulation in the matrix could lead to swelling and eventual membrane rupture. Paradoxically, despite the critical importance of potassium channels and exchangers and their extensive research history, molecular identity of the key potassium transport systems such as the K⁺/H⁺ exchanger and the ATP-dependent potassium channel remains a subject of ongoing debate. Within this review and analysis of scientific publications, we outline a number of unresolved issues related to potassium transport in mitochondria: incomplete knowledge of structural and functional rearrangements in mitochondria upon potassium ion influx and swelling; ambiguity surrounding molecular identity of the key potassium transport systems – the K⁺/H⁺ exchanger and the ATP-dependent potassium channel, as well as uncertain role of ATP synthase in ion transport; and the apparent underestimation of the role of the lipid component of the membrane in direct potassium transport and its regulation. We highlight that accumulation of lysocardiolipin, a derivative of the key mitochondrial lipid cardiolipin, in the membrane may represent a missing link crucial for constructing a comprehensive explanation of mitochondrial osmotic regulation mechanisms. Lysocardiolipin can form lipid pores that significantly enhance membrane conductance for cations. Accumulation of lysocardiolipin could be stimulated by lipid peroxidation, could alter membrane properties, and modulate assembly and function of the proteinaceous ion transporters. Accounting for the changes in physical (pressure, lipid packing) and chemical properties of the membrane (peroxidation, deacylation) during conditions that activate osmotic regulation systems is necessary for forming a holistic understanding of potassium transport mechanisms.

The quantitative content of mitochondrial DNA (mtDNA) – a multicopy circular genome – is an important parameter relevant for function of mitochondrial oxidative phosphorylation (OxPhos) in cells, since mtDNA encodes 13 essential OxPhos proteins, 22 tRNAs, and 2 rRNAs. In contrast to the nuclear genome, where almost all lesions have to be repaired, the multicopy nature of mtDNA allows the degradation of severely damaged genomes. Therefore, cellular mtDNA maintenance and its copy number not only depend on replication speed and repair reactions. The speed of intramitochondrial mtDNA degradation performed by a POLGexo/MGME1/TWNK degradation complex and the breakdown rate of entire mitochondria (mitophagy) are also relevant for maintaining the required steady state levels of mtDNA. The present review discusses available information about the processes relevant for turnover of mitochondrial DNA, which dysbalance leads to mtDNA maintenance disorders. This group of mitochondrial diseases is defined by pathological decrease of cellular mtDNA copy number and can be separated in diseases related to decreased mtDNA synthesis rates (due to direct replication defects or mitochondrial nucleotide pool dysbalance) or diseases related to increased breakdown of entire mitochondria (due to elevated mitophagy rates).

The naked mole rat is considered a unique non-aging mammalian species and is widely used in laboratories to study the biology of longevity. Previously, our group was the first to describe a new fatal disease in the naked mole rat, termed “idiopathic cachexia.” A detailed study of pathological changes in the organs of affected animals, combined with the data on gene expression changes, allows us to interpret this disease as a highly specific variant of accelerated aging (progeroid syndrome or progeria) in these animals. Symptoms of the disease include cachexia, cataracts, lipofuscinosis, and appearance of amyloid bodies (corpora amylacea) in the brain, severe degeneration of cardiomyocytes, fatty degeneration, and generalized lipofuscinosis of the liver and kidneys, with signs of autophagy dysfunction in these organs. Further research is needed to elucidate the mechanism of this disease in animals with negligible aging, such as naked mole rats, which may provide insights into the mechanisms of aging and lifespan extension.

Being among the most metabolically active organs, brain and kidneys critically depend on efficient energy metabolism, which primarily relies on oxidative phosphorylation. Acute pathological conditions associated with a lack of metabolic substrates or their impaired utilization trigger signaling cascades that initiate cell death and lead to poorly reversible organ dysfunction. One of the therapeutic approaches to correct the energy deficit is administration of exogenous metabolites of the tricarboxylic acid cycle, such as succinate. In this study, we investigated the effects of exogenous succinate on astrocytes and renal epithelial cells under normal conditions and in serum deprivation-induced injury. Incubation with succinate increased the viability of both cell types under normal and pathological conditions, but a more pronounced cytoprotective effect was observed in renal cells. In injured renal epithelial cells, succinate increased mitochondrial membrane potential, a critical parameter for the maintenance of mitochondrial function and ATP generation. Comparison of respiration and oxidative phosphorylation parameters in astrocytes and renal epithelial cells in the presence of exogenous succinate revealed that epithelial cells exhibited a significantly higher respiratory control and lower proton leak compared to astrocytes, which correlated with the higher cytoprotective activity of succinate for kidney cells. Therefore, succinate showed a noticeable positive effect in the renal epithelium both under normal conditions and after serum deprivation; however, in astrocytes, its effect was less pronounced. This discrepancy might be related to a more efficient succinate utilization by the mitochondria in renal cells and intrinsic bioenergetic differences between astrocytes and epithelial cells. Despite the clinical use of succinate-containing drugs, the determination of optimal dosages and development of effective therapeutic regimens require further investigation. Our results demonstrate cell type-dependent differences in the efficacy of succinate, suggesting that its therapeutic potential may differ significantly depending on the organ-specific bioenergetic and metabolic properties.

Acquired drug resistance reduces the effectiveness of anticancer therapy and leads to cancer progression. Selective inhibition of anti-apoptotic proteins of the Bcl-2 family using BH3-mimetics is a promising treatment strategy for cancer patients. Recently, antagonists of the anti-apoptotic protein Mcl-1 have been actively studied in clinical trials. However, like other BH3-mimetics, they can lose their effectiveness due to the development of acquired resistance. We have found that cancer cells develop resistance to Mcl-1 inhibition through increased gene expression of other anti-apoptotic proteins, such as Bcl-2 or Bcl-xL, thereby becoming less Mcl-1-dependent. Alterations in cellular metabolism have also accompanied the development of this resistance. We have shown that combining the Mcl-1 antagonist S63845 with various anticancer compounds can overcome the resistance of malignant cells to its action.