Objectives: Metabolic substrate deficiency is a key factor in many pathologies, with organ vulnerability depending on specialized metabolic profiles. In this study, we aimed to investigate the impact of deprivation stress on mitochondria and cell functions in different cell types and to assess the potential of fumarate, a tricarboxylic acid (TCA) cycle intermediate, to modulate these stress responses. Methods: We assessed the effects of fumarate on cell proliferation and mitochondrial membrane potential under both normal conditions and serum deprivation in vitro in astrocytes, renal epithelial cells, and hepatic stellate cells. Subsequently, we performed bioinformatic analysis of transcriptomic data for brain, kidney, and liver tissues subjected to ischemia to reveal specific patterns of alterations in energy metabolism. Results: Analysis of mitochondria-associated gene expression revealed striking organ-specific differences in transcriptional responses to ischemia, with a significant decrease in expression of genes related to the TCA cycle and electron transport chain in the kidneys and liver, in contrast to the brain. In an in vitro serum deprivation model, fumarate preserved mitochondrial potential in a cell type-specific manner, with optimal concentrations of 12.5 mM for astrocytes (p < 0.05), and 25 mM for renal (p < 0.01) or hepatic cells (p < 0.01). Under normal conditions, fumarate increased mitochondrial potential in astrocytes (p < 0.0001), with weak or no effect on renal and hepatic cells. Estimation of cell number indicates the effects of fumarate on the proliferation of kidney (p < 0.05) and liver (p < 0.0001) cells in normal conditions and cell death after serum deprivation. Conclusion: Bioinformatic analysis demonstrates that ischemic stress induces fundamentally different transcriptional programs in the brain, kidney, and liver, particularly affecting genes involved in mitochondrial bioenergetics. Complementing these findings, our in vitro data identify fumarate as a metabolically active but organ-dependent candidate for tissue protective strategies in substrate deprivation pathologies, like ischemia.

Background/Objectives: Inflammation and oxidative stress are key factors contributing to the initiation and progression of liver fibrosis in chronic obstructive cholestasis. Pantothenic acid (PA) and some of its derivatives have been reported to exhibit moderate anti-inflammatory, antioxidant, and regenerative effects. This study aimed to evaluate the redox-modulating effects of PA derivatives—panthenol (PL), pantethine (PT), and hopantenic acid (HPA) in a rat model of chronic obstructive cholestasis induced by common bile duct ligation (BDL). Methods: Macroscopic, histological, and ultrastructural alterations in the liver were assessed, along with molecular markers of oxidative stress, inflammation, and parameters of the glutathione (GSH) system. Results: BDL-induced liver injury was associated with enhanced lipid peroxidation, mitochondrial structural alterations, depletion of GSH, increased levels of protein S-glutathionylation (PSSG), and elevated thiobarbituric acid-reactive substances in mitochondria. Treatment with PL and, to a lesser extent, PT was associated with attenuation of hepatocellular ultrastructural damage, reduced bile duct hyperplasia, decreased inflammatory and necrotic changes, and moderate improvement in fibrosis-related parameters. In contrast, HPA (a PA antagonist) did not demonstrate hepatoprotective effects and it was associated with more pronounced liver injury. Conclusions: Chronic BDL is accompanied by suppression of glutathione redox capacity and enhanced oxidative stress. PL and PT, but not HPA, were associated with reduced levels of protein S-glutathionylation and partial restoration of redox balance. The protective effects of PL and PT may contribute to their antifibrotic activity, potentially through direct antioxidant capacity or redox-modulating mechanisms associated with the GSH system.

Drug-induced nephrotoxicity is a leading cause of acute kidney injury (AKI) and subsequent chronic kidney disease. Nephrotoxicity often develops as a consequence of treatment with commonly prescribed aminoglycoside antibiotics, and remains a significant clinical challenge. One approach to treating AKI and its associated complications is caloric restriction or its pharmacological mimetics. This study aimed to evaluate the effects of caloric restriction mimetic hydroxycitrate (HC) in gentamicin-induced nephrotoxicity, with particular focus on the influence of treatment duration and the underlying molecular mechanisms. In vitro renal tubular epithelial cells models were used to assess HC’s effects on viability, proliferation, and autophagy activation. For in vivo validation, rats with gentamicin-induced AKI received HC treatment via two distinct regimens (3-week and 7-week administration). Experiments on renal tubule cells showed that HC significantly increased cell viability and proliferation and led to the activation of autophagy. In the rat model, only the 7-week administration of HC demonstrated significantly attenuated renal dysfunction in gentamicin-induced AKI. Moreover, it reduced macrophage infiltration, increased renal cell tolerance to apoptosis, activated autophagy, and reduced oxidative stress. Thus, our results indicate that 7-week HC administration could be used as a prophylactic strategy against antibiotic nephrotoxicity, exerting its effects by promoting autophagy, resisting apoptosis, and attenuating oxidative damage.

We explored the possibility of antioxidant and antifibrotic effects of panthenol (PL) associated with modulation of coenzyme A (CoA) biosynthesis in the liver in a rat model of chronic obstructive cholestasis induced by bile duct ligation (BDL). We found that PL increased alcohol dehydrogenase (ADH) activity in the liver of BDL rats. PL and its analog pantethine increased pantothenate kinase (PANK) activity, restored hepatic CoA levels reduced by BDL, lowered protein-bound CoA, and normalized impaired mitochondrial functions associated with induced oxidative stress after BDL. These effects were accompanied by decreased collagen deposition and improved morphological features of hepatocytes. In contrast, PANK inhibitor, hopantenic acid (HPA), reduced hepatic CoA levels, aggravated hepatocellular damage, and promoted fibrosis. In the human hepatic stellate cell line LX-2, PL exhibited no cytotoxicity over a wide concentration range, increased intracellular CoA levels, decreased reactive oxygen species (ROS) production, and attenuated collagen accumulation associated with oxidative stress in vitro. Importantly, inhibition of ADH by 4-methylpyrazole completely abolished the protective effects of panthenol, indicating that its activity depends on metabolic pathways involving CoA. Notably, PL did not directly reduce H2O2 or superoxide anion radical production in cell-free systems but significantly suppressed lipid peroxidation in liposomes and red blood cells in vitro. Ultimately, these findings indicate that the antioxidant and antifibrotic effects of PL are associated with modulation of CoA metabolism and enhanced resistance of biological membranes to oxidative damage.

Caloric restriction (CR) is known to activate a broad spectrum of cytoprotective signaling pathways and enhance tissue tolerance to various stressors, including those associated with the cytotoxic effects of pharmaceutical agents. Nephrotoxic drugs, such as aminoglycoside antibiotics, remain a major clinical concern due to their frequent use and potential to cause acute kidney injury (AKI), for which effective preventive strategies are still limited. In this study, we investigated whether CR applied for 5 weeks (4-week pretreatment + 1-week concurrent with AKI induction) can alleviate AKI triggered by the antibiotic gentamicin, with a focus on evaluating changes in antioxidant-related parameters and autophagy-associated signaling during CR-mediated nephroprotection. CR’s nephroprotective effects were evaluated using diagnostic assays, Western blotting, and histological analysis. Additionally, oxidative stress markers and mitochondrial integrity were assessed to analyze the impact of CR on antioxidant-related pathways. CR significantly improved renal function and structure, with reduced kidney injury markers (KIM-1, NGAL) and alleviated histological damage. Critically, CR mitigated oxidative stress, evidenced by decreased thiobarbituric acid reactive substances (TBARS) and protein carbonylation, as well as increased levels of the reduced form of glutathione and activity of glutathione peroxidase (GPx). A lowered Bcl-XL/XS ratio was consistent with reduced apoptotic signaling, while reduced leukocyte infiltration reflected attenuated renal inflammation. Additionally, a reduction in mitochondrial DNA (mtDNA) lesions suggested that CR was associated with modulation of mitochondrial and metabolism-related pathways, with concurrent improvements in mitochondrial stability. Our findings demonstrate that CR attenuated gentamicin-induced AKI and was associated with changes in antioxidant-related parameters, reduced mtDNA damage, a decrease in inflammatory cell infiltration, and modulation of autophagy-related signaling.

Diabetes and obesity are associated with poorer outcomes after ischemic stroke; however, it remains unclear whether this results from increased neuronal susceptibility to injury or from vascular dysfunction induced by metabolic syndrome. To minimize the contribution of vascular factors, we used a model of photoinduced thrombosis (PT) in cortical vessels, which generates lesions of reproducible size and is less dependent on collateral blood flow. PT was induced in wild-type (WT) mice, as well as in ob/ob (leptin-deficient) and db/db (leptin receptor-deficient) mice. Magnetic resonance imaging (MRI) revealed that PT produced comparable infarct volumes in all mouse groups. Several genes associated with inflammation and activation of microglia and macroglia in the peri-infarct area (Cst7, Ccl3, Tlr2, Gfap) exhibited similar expression patterns across all three mouse strains, while transcriptional response to cerebral ischemia of Tnfa, Cxcl9, Il6, Cox2, Mmp3, and Bdnf genes depended on the genotype. Overall, despite individual differences in the expression profiles of certain genes, disruption of leptin signaling (whether due to leptin deficiency or leptin receptor deficiency) caused no genotype-specific exacerbation of stroke-induced injury. Assessment of post-stroke neurological deficits revealed substantial differences in absolute scores between WT and ob/ob or db/db mice, attributable to baseline disparities in body weight and motor activity. In db/db mice, normalization of post-stroke neurological status scores to pre-injury values revealed a more pronounced relative functional decline compared to ob/ob mice, suggesting impairments in early compensatory mechanisms and an important role of leptin signaling in neuroplasticity rather than in the extent of acute neuronal damage. Thus, under conditions that minimize vascular complications, neither leptin deficiency nor leptin receptor deficiency exacerbated acute ischemic brain damage or neuroinflammation.

Ischemia–reperfusion (I/R) injury is a complex pathological process underlying numerous acute organ failures and is a significant cause of morbidity and mortality in diseases such as myocardial infarction, stroke, thrombosis, and organ transplantation. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have demonstrated considerable therapeutic potential, but their broad tropism and general repair signaling may limit their efficacy. This review addresses the emerging paradigm of using organ-specific EVs for the treatment of I/R injury in the respective organs. We summarize the existing studies performed on experimental animals showing that these native EVs could possess tissue tropism and carry a specialized cargo of proteins, miRNAs, and lipids tailored to the unique regenerative needs of their organ of origin, enabling them to precisely modulate key processes, including inflammation, apoptosis, oxidative stress, and angiogenesis. However, their clinical translation faces challenges related to scalable production, standardization, and the dualistic nature of their effects, which can be either protective or detrimental, depending on the cellular source and pathophysiological context. Future developments need to focus on overcoming these obstacles through rigorous isolation protocols, engineering strategies such as cargo enrichment and hybrid vesicle creation, and validation in large-animal models. Overall, organ-specific EVs offer a novel, cell-free therapeutic strategy with the potential to significantly improve outcomes in I/R injury.

Background: Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer's disease (AD). Resveratrol is a promising compound for the treatment of various neurodegenerative diseases, including AD. Aims: To investigate mitochondrial damage and the effects of resveratrol on inflammation, cognitive function, and mitochondrial quality control in APP/PS1 mice. Methods: Comparative analysis of mitochondrial DNA (mtDNA) damage was conducted between 10-month-old APP/PS1 mice and age-matched C57BL/6 mice. Assessments included measurement of amyloid-beta levels, inflammatory markers, swimming distance in the Morris water maze, and gut microbiome composition. Resveratrol's effects on cytokine expression, mtDNA levels in plasma, and activation of Nuclear factor erythroid 2-related factor 2/Antioxidant response element (Nrf2/ARE) and phosphoinositide 3-kinase/protein kinase B (also known as Akt)/mechanistic target of rapamycin complex 1 (PI3K/Akt/mTORC1) signaling pathways were also evaluated. Results: APP/PS1 mice exhibited significantly increased mtDNA damage in the prefrontal cortex, midbrain, and cerebellum, alongside higher amyloid-beta levels and inflammatory markers. Resveratrol treatment led to reduced expression of pro-inflammatory cytokines, a decrease in Proteobacteria levels, and lower cellfree mtDNA in plasma. Partial improvement in long-term spatial memory was observed in APP/PS1 mice following resveratrol treatment, likely due to its anti-inflammatory properties. Activation of the Nrf2/ARE signaling pathway and markers of PI3K/Akt/mTORC1 axis activation were noted, with the latter regulating long-term potentiation. Conclusion: Resveratrol demonstrates potential in mitigating inflammation and improving mitochondrial quality control in APP/PS1 mice, but it does not reduce amyloid-beta levels, highlighting the complexity of AD pathology and the need for further research.

BACKGROUND:Mesenchymal stem/stromal cells (MSCs) are the focus of increasing research as a potential therapeutic agent for a range of nervous system diseases, due to their unique capacity for self-renewal and differentiation. The subsequent tracking of cells post-transplantation into the organism is of pivotal significance, as it elucidates their fate, distribution, and enables the timely monitoring of any adverse effects. In the context of cell monitoring, the utilization of a non-toxic label that exhibits long-term stability is of paramount importance. METHODS:A human immortalized MSCs cell line was engineered to express a green fluorescent protein (GFP) and bacterial nanocompartments (high-molecular-weight icosahedral capsid-like protein complexes) via lentiviral transduction. The obtained cells were characterized by inductively coupled plasma mass spectrometry (ICP-MS) and Perls staining as well as using the nonlinear magnetization method, confocal microscopy and flow cytometry. An animal study was conducted in Sprague-Dawley rats. RESULTS:In this study, an immortalized human MSCs cell line with stable expression of a novel magnetic resonance (MR) reporter label was established for the first time. GFP was genetically produced for utilization as an optical tag. A nanocompartment of the bacterium Quasibacillus thermotolerans (Qt) was used as a carrier of the magnetic label. The Qt nanocompartment consists of a shell and a ferroxidase cargo protein. Ferroxidase provides the biomineralization of iron ions within the nanocompartment shell. As a result, ferric oxide nanoparticles are formed inside the encapsulin nanocompartments, which have T2-contrast properties and serve as genetically encoded labels for magnetic resonance imaging (MRI) and for quantification by the nonlinear magnetization method. CONCLUSIONS:The experimental results indicate that the use of two complementary labels allows for the multimodal visualization of the derived cells post-transplantation into the rat brain striatum, which is promising for monitoring MSCs-based therapy.

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.

The ketogenic diet (KD) has been shown to be effective in treating various brain pathologies. In this study, we conducted detailed transcriptomic and metabolomic profiling of rat brains after KD and ischemic stroke in order to investigate the effects of KD and its underlying mechanisms. We evaluated the effect of a two-month KD on gene expression in intact brain tissue and after middle cerebral artery occlusion (MCAO). We analyzed the effects of KD on gut microbiome composition and blood metabolic profile as well as investigated the correlation between severity of neurological deficits and KD-induced changes. We found transcriptional reprogramming in the brain after stroke and KD treatment. The KD altered the expression of genes involved in the regulation of glucose and fatty acid metabolism, mitochondrial function, the immune response, Wnt-associated signaling, stem cell development, and neurotransmission, both in intact rats and after MCAO. The KD led to a significant change in the composition of gut microbiome and the levels of amino acids, acylcarnitines, polyunsaturated fatty acids, and oxylipins in the blood. However, the KD slightly worsened the neurological functions after MCAO, so that the therapeutic effect of the diet remained unproven.

Obstructive nephropathy is a common clinical condition caused by urinary retention. After urine flow is restored, kidney function is recovered. However, the effectiveness of this process can be influenced by many factors, including the age of the patient. In this study, we analyzed the following parameters in young and old rats subjected to a 3-day reversible unilateral ureteral obstruction (R-UUO): AKI severity, renal tissue proliferation and histology, inflammatory and fibrosis marker expression, as well as autophagosomal-lysosomal and mitochondrial function. Compared to old rats, young animals exhibited more pronounced renal tissue proliferation and higher expression of profibrotic markers (Col1a1, Fn1, Tgfb1, MMP2), but diminished expression of pro-inflammatory markers (Il1b, Tnfa, Cd32) in response to R-UUO. Additionally, young rats showed more pronounced activity of autophagy, as indicated by increased beclin-1 levels. R-UUO induced severe damage to the mitochondrial respiratory chain in old animals, as indicated by reduced complex I, IV, cytochrome c, VDAC protein levels, and impaired mitochondrial biogenesis (associated with decreased Pgc1a mRNA expression). Thus, we demonstrated that despite restored urine outflow, kidneys exhibited autophagy activation, inflammatory response, and mitochondrial dysfunction after R-UUO. Negative alterations in the kidney were age-dependent indicating necessity for therapeutic strategies optimization for patients of different ages.

Redox potential controls a vast array of biochemical reactions, and its changes influence the transition from normal to pathological states. However, cellular redox potential is primarily assessed after extraction of water-soluble components (reduced and oxidized) from biological material, particularly glutathione, which, due to its abundance, determines intracellular redox potential. This process involves mechanistic averaging of redox potential values across tissue or cell, although existing data suggest, and sometimes directly indicate, heterogeneity in redox potential both within cells and within tissue. We argue that mitochondria determine cellular redox state, in particular through changes in the state of the mitochondrial reticulum caused by various internal and external factors. We describe the possibilities for regulation of redox status of the cell and organ as a potential therapy for various pathologies, particularly cancer, and propose intensifying efforts to utilize intrinsic redox indicators. We specifically examine the possibility of changes the redox potential in cancer cells through the use of oxidative phosphorylation uncouplers and propose mechanisms by which cancer cells may be killed using uncouplers. Particular attention is paid to the mitochondrial membrane potential as a powerful regulator of cellular metabolism, possibly unrelated to the regulation of reactive oxygen species levels, with the possible existence of a membrane potential sensor in cells.

Undesirable tissue fibroblast activation after injury is still an unresolved problem for many organs, including the kidney. Kidney fibroblasts and tubular epithelial cells demonstrate significant differences in gene expression profiles, including metabolism-related genes. As a result, these cell types exhibit differences in the energy metabolism that could be the basis of targeted therapy for fibrosis. Among other deacetylase inhibition is considered a therapeutic approach that could simultaneously promote tissue regeneration and suppress the development of fibrosis, but their relation to bioenergetics has not been considered before. In this study, we aimed to compare the influence of the HDAC inhibitor trichostatin A (TSA) on renal tubular epithelial cells and kidney fibroblasts. We analyzed resemblance and differences in TSA effects on the proliferative activity of the cells and investigated the molecular mechanisms responsible for these effects; e.g., we focused on the activity of signaling pathways associated with cell viability (Akt/mTOR/p70S6). We found that TSA increased the proliferation rate of epithelial cells, while it tended to decrease the growth rate of fibroblasts. Furthermore, the amount of phosphorylated forms of kinases Akt and P70S6 increased in epithelial cells after incubation with TSA, indicating the activation of the Akt/mTOR/p70S6 signaling pathway, while decreasing its activity in fibroblast cells. Since there are differences in the bioenergetics between fibroblasts and epithelial cells, we investigated the impact of TSA on the glycolytic activity of both cell types. Indeed, we showed that TSA reduced the activity of glycolytic processes in fibroblast cells. The observed changes indicate a positive effect of TSA on regenerative versus fibrotic processes in the kidney by reducing the growth and metabolic activity of fibroblasts and activating the proliferation of epithelial cells.

Alzheimer’s disease is a complex neurodegenerative disease based on various processes associated with the accumulation and aggregation of defective proteins. Among them, the particularly important ones are the following: amyloid-β, which is formed by the breakdown of amyloid precursor protein, the accumulation of hyperphosphorylated tau proteins inside neurons that form neurofibrillary tangles, and aberrant aggregation and inclusion formation of microtubule-associated protein tau (MAPT). APP/PS1 transgenic mice act as a model of Alzheimer’s disease and express mutant human genes that cause the accumulation of amyloid-β peptides in the brain. The goal of this work was a quantitative assessment of the level of p-tau231 in the brain of transgenic mice with a model of AD using the sorption method. The objectives of the study also included testing the ability of the natural polyphenol resveratrol to reduce the concentration of p-tau231 in the brain of transgenic mice and improve their cognitive functions. Western blot is a widely used method for the immunodetection and in vitro quantitative determination of proteins. Western blot allows separating proteins based on their molecular weight with the further transfer to an adsorption membrane. In this case, the proteins are transferred from the gel to the PVDF membrane using electrophoretic elution. This method involves placing a protein-containing polyacrylamide gel in direct contact with a PVDF membrane represented by a linear polymer with repetitive links -(CF2-CH2)-. Proteins transferred to the membrane are well-retained on its surface during the whole immunodetection process due to a combination of dipole and hydrophobic interactions. Western blot showed that mice with impaired protein aggregation accumulated significantly more MAPT and phosphorylated tau protein in the brain as compared to wild mice. In addition, in the course of the Morris water maze test, these mice showed cognitive deficits, which manifested both in the difficulty of finding the platform and more anxious behaviour, which confirmed pronounced thigmotaxis. The natural polyphenol resveratrol partially reversed cognitive deficits, although this effect was not associated with decreased levels of phosphorylated tau and MAPT.

The aim of this work was to test whether we can treat cholestasis with dietary approaches applied after the onset of the disease. The effects of intermittent fasting and dietary restriction on liver damage caused by common bile duct ligation (BDL) in rats were studied, with particular attention paid to changes in the activity of enzymes of energy metabolism and antioxidant protection. Morphological changes in liver tissue and serum markers of liver damage were assessed in rats with BDL kept for one month on ad libitum diet, intermittent fasting, or 35% dietary restriction. We studied parameters of glucose metabolism (activity of glycolysis and gluconeogenesis enzymes), TCA cycle, and indicators of oxidative stress and redox status of the liver tissue. Dietary restriction resulted in an increase in gluconeogenesis activity, antioxidant capacity, and autophagy activation. When implemented after BDL, none of the dietary restriction protocols reduced the level of oxidative stress, detrimental morphological and biochemical alterations, or the fibrosis progression. Thus, under severe damage and oxidative stress developing in cholestasis, dietary restrictions are not hepatoprotective and can only be used in a pre-treatment mode.

There is an increasing accumulation of data on the exceptional importance of mitochondria in the occurrence and treatment of cancer, and in all lines of evidence for such participation, there are both energetic and non-bioenergetic functional features of mitochondria. This analytical review examines three specific features of adaptive mitochondrial changes in several malignant tumors. The first feature is characteristic of solid tumors, whose cells are forced to rebuild their energetics due to the absence of oxygen, namely, to activate the fumarate reductase pathway instead of the traditional succinate oxidase pathway that exists in aerobic conditions. For such a restructuring, the presence of a low-potential quinone is necessary, which cannot ensure the conventional conversion of succinate into fumarate but rather enables the reverse reaction, that is, the conversion of fumarate into succinate. In this scenario, complex I becomes the only generator of energy in mitochondria. The second feature is the increased proliferation in aggressive tumors of the so-called mitochondrial (peripheral) benzodiazepine receptor, also called translocator protein (TSPO) residing in the outer mitochondrial membrane, the function of which in oncogenic transformation stays mysterious. The third feature of tumor cells is the enhanced retention of certain molecules, in particular mitochondrially directed cations similar to rhodamine 123, which allows for the selective accumulation of anticancer drugs in mitochondria. These three features of mitochondria can be targets for the development of an anti-cancer strategy.

We demonstrated that the serum of pregnant rats increases viability of kidney epithelial cells and promotes their proliferation. The intensity of oxidative stress in the kidneys was also reduced during pregnancy, but only in rats that were not exposed to acute ischemic kidney injury. This decrease in oxidative stress was not associated with changes in transmembrane mitochondrial potential, the size of mitochondria, time of opening of mitochondrial permeability transition pore (mPTP), mitochondrial respiration rate, antioxidant activity, or nitric oxide level.

The positive effects of female sex hormones, particularly estradiol and progesterone, have been observed in treatment of various pathologies. Acute kidney injury (AKI) is a common condition in hospitalized patients in which the molecular mechanisms of hormone action are poorly characterized. In this study, we investigated the influence of estradiol and progesterone on renal cells during ischemic injury. We performed both in vivo experiments on female and male rats and in vitro experiments on renal tubular cells (RTCs) obtained from the kidneys of intact animals of different sexes. Since mitochondria play an important role in the pathogenesis of AKI, we analyzed the properties of individual mitochondria in renal cells, including the area, roundness, mitochondrial membrane potential, and mitochondrial permeability transition pore (mPTP) opening time. We found that pre-treatment with progesterone or estradiol attenuated the severity of ischemia/reperfusion (I/R)-induced AKI in female rats, whereas in male rats, these hormones exacerbated renal dysfunction. We demonstrated that the mPTP opening time was higher in RTCs from female rats than that in those from male rats, which may be one of the reasons for the higher tolerance of females to ischemic injury. In RTCs from the kidneys of male rats, progesterone caused mitochondrial fragmentation, which can be associated with reduced cell viability. Thus, therapy with progesterone or estradiol displays quite different effects depending on sex, and could be only effective against ischemic AKI in females.

Worldwide, interest in mitochondria is constantly growing, as evidenced by scientific statistics, and studies of the functioning of these organelles are becoming more prevalent than studies of other cellular structures. In this analytical review, mitochondria are conditionally placed in a certain cellular center, which is responsible for both energy production and other non-energetic functions, without which the existence of not only the eukaryotic cell itself, but also the entire organism is impossible. Taking into account the high multifunctionality of mitochondria, such a fundamentally new scheme of cell functioning organization, including mitochondrial management of processes that determine cell survival and death, may be justified. Considering that this issue is dedicated to the memory of V. P. Skulachev, who can be called mitocentric, due to the history of his scientific activity almost entirely aimed at studying mitochondria, this work examines those aspects of mitochondrial functioning that were directly or indirectly the focus of attention of this outstanding scientist. We list all possible known mitochondrial functions, including membrane potential generation, synthesis of Fe–S clusters, steroid hormones, heme, fatty acids, and CO2. Special attention is paid to the participation of mitochondria in the formation and transport of water, as a powerful biochemical cellular and mitochondrial regulator. The history of research on reactive oxygen species that generate mitochondria is subject to significant analysis. In the section “Mitochondria in the Center of Death”, special emphasis is placed on the analysis of what role and how mitochondria can play and determine the program of death of an organism (phenoptosis) and the contribution made to these studies by V. P. Skulachev.