Vol 90, No 12 (2025)

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 and depolarization of the inner membrane. These processes are accompanied by a dysregulation of ion homeostasis, damage to mitochondrial membranes and, ultimately, cell death. Despite decades of research, the molecular identity of the MPT pore remains unclear. Recently, its key structural components, along with the regulatory protein cyclophilin D, are considered to be the inner membrane proteins ATP synthase and adenine nucleotide translocator (ANT). 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 the interpretation as a simple experimental artifact to the recognition of a putative key regulator of energy metabolism — and also considers the mechanisms of its regulation and pathophysiological role.

Antibiotics are certainly the most important agents in the fight against human and animal bacterial infections. The widespread use of antibiotics has a positive impact on the treatment of infectious diseases but may be accompanied by serious side effects. The clinical aspects of these side effects are well understood, but the 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, known stimuli of cellular senescence. On the other hand, the same stimuli can induce death of senescent cells. Thus, mitotoxic antibiotics may influence both the cellular senescence process and the 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 researchers' attention to the possibility of accelerated cellular aging induced by common antibacterial antibiotics and to discuss the potential mechanisms behind this phenomenon.

Mitochondria play a central role in cell physiology, and in addition to performing their primary function as an energy source, they are involved in processes such as regulating intracellular calcium levels, generating reactive oxygen species, synthesizing many critical compounds, regulating apoptosis, and more. In this regard, maintaining them in a normal state is of great importance, ensuring their transport, intracellular distribution, timely biogenesis, and removal of damaged mitochondria from cells. All of this is defined as cellular mitosis, the maintenance of which involves many cellular structures and, primarily, the cytoskeleton. This review summarizes data on the role of one component of the cytoskeleton, vimentin intermediate filaments, in these processes.

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.

In the 70s and 80s of the last century, the presence of the mitochondrial reticulum in skeletal muscles has been outlined. The concept functioning this reticulum in a cell to deliver energy throughout the cell volume in the form of a transmembrane potential built on the inner membrane of mitochondria, followed by the synthesis of ATP by mitochondrial ATP synthase, was put forth and proved. However, evidence based on studies of mitochondrial ultrastructure remains subject to criticism. To exclude the possibility of artifacts caused by the preparation of the sample for electron microscopy, the mitochondrial structure detected in ultrathin sections of muscle fiber used in electron microscopy and the structure in intact fiber were compared with the visualization of mitochondria with a membrane potential- dependent dye. This comparison was carried out for two species: mice and the naked mole rat, known for its extraordinary longevity. Full compliance with the previously made conclusions about the structure of the mitochondrial reticulum has been obtained. An additional model of the functioning of giant mitochondria as intracellular structures that prevent hypoxia in tissues is proposed.

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 efficiency of cancer treatment and leads to cancer progression. The selective inhibition of antiapoptotic proteins from the Bcl-2 family by BH3 mimetics is a promising strategy for the treatment of cancer patients. In recent years, antagonists of the antiapoptotic protein Mcl-1 have been intensively studied in clinical trials; however, like other BH3 mimetics, they may lose their effectiveness due to the development of acquired resistance. We have found that tumor cells develop resistance to Mcl-1 inhibition due to increased expression of genes of other antiapoptotic proteins (Bcl-2 or Bcl-xL), becoming less Mcl-1-dependent. The development of this type of resistance can also be accompanied by changes in cell metabolism. We have shown that combining Mcl-1 antagonist S63845 and various antitumor compounds can lead to overcoming the resistance of malignant cells to its action.