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Restenosis, defined as the re-narrowing of an arterial lumen after revascularization, represents an increasingly important issue in clinical practice. Indeed, as the number of stent placements has risen to an estimate that exceeds 3 million annually worldwide, revascularization procedures have become much more common. Several investigators have demonstrated that vessels in patients with diabetes mellitus have an increased risk restenosis. Here we present a systematic overview of the effects of diabetes on in-stent restenosis. Current classification and updated epidemiology of restenosis are discussed, alongside the main mechanisms underlying the pathophysiology of this event. Then, we summarize the clinical presentation of restenosis, emphasizing the importance of glycemic control in diabetic patients. Indeed, in diabetic patients who underwent revascularization procedures a proper glycemic control remains imperative., (© 2022. The Author(s).)

Sortilin is a glycoprotein mainly known for its role as a trafficking molecule directing proteins to specific secretory or endocytic compartments of the cell. Its actual contribution to essential hypertension has remained hitherto elusive. Combining top-notch in vivo, ex vivo, and in vitro approaches to clinical investigations, Di Pietro et al. explored the signaling pathway evoked by sortilin in endothelial cells and report on such exploration in this issue of the JCI. The researchers identified circulating sortilin as a biomarker associated with high blood pressure. Mechanistically, they demonstrate that sortilin altered sphingolipid/ceramide homeostasis, initiating a signaling cascade that, from sphingosine-1-phosphate (S1P), leads to the augmented production of reactive oxygen species. Herein, we discuss the main implications of these findings, and we anticipate some of the potential avenues of investigation prompted by this discovery, which could eventually lead to treatments for cardiometabolic disorders.

Heart failure and cardiovascular disorders represent the leading cause of death in diabetic patients. Here we present a systematic review of the main mechanisms underlying the development of diabetic cardiomyopathy. We also provide an excursus on the relative contribution of cardiomyocytes, fibroblasts, endothelial and smooth muscle cells to the pathophysiology of heart failure in diabetes. After having described the preclinical tools currently available to dissect the mechanisms of this complex disease, we conclude with a section on the most recent updates of the literature on clinical management., Competing Interests: Declaration of competing interest Nothing to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

l-Arginine is involved in many different biological processes and recent reports indicate that it could also play a crucial role in the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present an updated systematic overview of the current evidence on the functional contribution of L-Arginine in COVID-19, describing its actions on endothelial cells and the immune system and discussing its potential as a therapeutic tool, emerged from recent clinical experimentations.

Substantial evidence indicates that microRNA-155 (miR-155) plays a crucial role in the pathogenesis of diabetes mellitus (DM) and its complications. A number of clinical studies reported low serum levels of miR-155 in patients with type 2 diabetes (T2D). Preclinical studies revealed that miR-155 partakes in the phenotypic switch of cells within the islets of Langerhans under metabolic stress. Moreover, miR-155 was shown to regulate insulin sensitivity in liver, adipose tissue, and skeletal muscle. Dysregulation of miR-155 expression was also shown to predict the development of nephropathy, neuropathy, and retinopathy in DM. Here, we systematically describe the reports investigating the role of miR-155 in DM and its complications. We also discuss the recent results from in vivo and in vitro models of type 1 diabetes (T1D) and T2D, discussing the differences between clinical and preclinical studies and shedding light on the molecular pathways mediated by miR-155 in different tissues affected by DM.

Neuropilin-1 is a transmembrane glycoprotein that has been implicated in several processes including angiogenesis and immunity. Recent evidence has also shown that it is implied in the cellular internalization of the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19). We hypothesized that specific microRNAs can target Neuropilin-1. By combining bioinformatic and functional approaches, we identified miR-24 as a regulator of Neuropilin-1 transcription. Since Neuropilin-1 has been shown to play a key role in the endothelium-mediated regulation of the blood-brain barrier, we validated miR-24 as a functional modulator of Neuropilin-1 in human brain microvascular endothelial cells (hBMECs), which are the most suitable cell line for an in vitro blood-brain barrier model.

We studied the development of acute kidney injury and animal death in the model of combined injury caused by kidney ischemia/reperfusion with simultaneous systemic administration of mitochondria. It was found that intraperitoneal injection of isolated mitochondria led to the appearance of mitochondrial DNA in the peripheral blood that could activate innate immunity. After administration of mitochondria, as well as after renal ischemia/reperfusion, proinflammatory changes were observed, primarily leukocytosis and granulocytosis. The combination of ischemia/reperfusion with injection of mitochondria caused a sharp increase in animal death, which may indicate a direct link between activation of TLR-signaling and high mortality of patients with combined injuries and multiple-organ failure in intensive care units. Treatment with mitochondria-targeted antioxidant increased animal survival, which indicated the participation of mitochondrial ROS in the development of systemic inflammatory response and death caused by acute renal failure.

Macrophage migration inhibitory factor (MIF) is a cytokine expressed in various cell types, including hematopoietic, epithelial, endothelial, mesenchymal and neuronal cells. Altered MIF expression has been associated with a multitude of diseases ranging from inflammatory disorders like sepsis, lupus and rheumatoid arthritis to organ pathologies such as heart failure, myocardial infarction, acute kidney injury, organ fibrosis and a number of malignancies. The implication of MIF in these diseases was supported by numerous animal studies. MIF acts in an autocrine and paracrine manner via binding and activating the receptors CD74/CD44, CXCR2, CXCR4 and CXCR7. Upon receptor binding, several downstream signaling pathways were shown to be activated in vivo, including ERK1/2, AMPK and AKT. Expression of MIF receptors is not uniform in various cells, resulting in differential responses to MIF across various tissues and pathologies. Within cells, MIF can directly bind and interact with intracellular proteins, such as the constitutive photomorphogenic-9 (COP9) signalosome subunit 5 (CSN5), p53 or thioredoxin-interacting protein (TXNIP). D-dopachrome tautomerase (D-DT or MIF-2) was recognized to be a structural and functional homolog of MIF, which could exert overlapping effects, raising further the complexity of canonical MIF signaling pathways. Here, we provide an overview of the expression and regulation of MIF, D-DT and their receptors. We also discuss the downstream signaling pathways regulated by MIF/D-DT and their pathological roles in different tissue, particularly in the heart and the kidney., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Dietary restriction (DR) is one of the most efficient approaches ameliorating the severity of different pathological conditions including aging. We investigated the protective potential of short-term DR in the model of acute kidney injury (AKI) in young and old rats. In kidney tissue, the levels of autophagy and mitophagy were examined, and proliferative properties of renal cells obtained from rats of different age were compared. DR afforded a significant nephroprotection to ischemic kidneys of young rats. However, in old rats, DR did not provide such beneficial effect. On the assessment of the autophagy marker, the LC3 II/LC3 I ratio, and after staining the tissue with LysoTracker Green, we concluded that in old rats activity of the autophagic-lysosomal system decreased. Mitophagy, as assessed by the levels of PINK-1, was also deteriorated in old animals. Renal cells from old rats showed impaired proliferative capacity, a worse rate of recovery after ischemic injury, increased levels of oxidative stress, accumulation of lipofuscin granules and lower mitochondria membrane potential. The results suggest that the loss of DR benefits in old animals could be due to deterioration in the autophagy/mitophagy flux., Competing Interests: The authors declare no conflict of interest.

The mitochondrial membrane potential (ΔΨm) generated by proton pumps (Complexes I, III and IV) is an essential component in the process of energy storage during oxidative phosphorylation. Together with the proton gradient (ΔpH), ΔΨm forms the transmembrane potential of hydrogen ions which is harnessed to make ATP. The levels of ΔΨm and ATP in the cell are kept relatively stable although there are limited fluctuations of both these factors that can occur reflecting normal physiological activity. However, sustained changes in both factors may be deleterious. A long-lasting drop or rise of ΔΨm vs normal levels may induce unwanted loss of cell viability and be a cause of various pathologies. Among other factors, ΔΨm plays a key role in mitochondrial homeostasis through selective elimination of dysfunctional mitochondria. It is also a driving force for transport of ions (other than H + ) and proteins which are necessary for healthy mitochondrial functioning. We propose additional potential mechanisms for which ΔΨm is essential for maintenance of cellular health and viability and provide recommendations how to accurately measure ΔΨm in a cell and discuss potential sources of artifacts., (Copyright © 2017. Published by Elsevier Inc.)

The anti-aging strategy is one of the main challenges of the modern biomedical science. The term "aging" covers organisms, cells, cellular organelles and their constituents. In general term, aging system admits the existence of nonfunctional structures which by some reasons have not been removed by a clearing system, e.g., through autophagy/mitophagy marking and destroying unwanted cells or mitochondria. This directly relates to the old kidney which normal functioning is critical for the viability of the organism. One of the main problems in biomedical studies is that in their majority, young organisms serve as a standard with further extrapolation on the aged system. However, some protective systems, which demonstrate their efficiency in young systems, lose their beneficial effect in aged organisms. It is true for ischemic preconditioning of the kidney, which is almost useless for an old kidney. The pharmacological intervention could correct the defects of the senile system provided that the complete understanding of all elements involved in aging will be achieved. We discuss critical elements which determine the difference between young and old phenotypes and give directions to prevent or cure lesions occurring in aged organs including kidney., Abbreviations: AKI: acute kidney injury; I/R: ischemia/reperfusion; CR: caloric restriction; ROS: reactive oxygen species; RC: respiratory chain.

Current methods for treatment of cellular and organ pathologies are extremely diverse and constantly evolving, going beyond the use of drugs, based on chemical interaction with biological targets to normalize the functions of the system. Because pharmacological approaches are often untenable, recent strategies in the therapy of different pathological conditions are of particular interest through introducing into the organism of some living system or its components, in particular, bacteria or isolated subcellular structures such as mitochondria. This review describes the most interesting and original examples of therapy using bacteria and mitochondria, which in perspective can dramatically change our views on the principles for the treatment of many diseases. Thus, we analyze such therapeutic effects from the perspective of the similarities between mitochondria and bacteria as the evolutionary ancestors of mitochondria.

Fragmentation (fission) of mitochondria, occurring in response to oxidative challenge, leads to heterogeneity in the mitochondrial population. It is assumed that fission provides a way to segregate mitochondrial content between the "young" and "old" phenotype, with the formation of mitochondrial "garbage," which later will be disposed. Fidelity of this process is the basis of mitochondrial homeostasis, which is disrupted in pathological conditions and aging. The asymmetry of the mitochondrial fission is similar to that of their evolutionary ancestors, bacteria, which also undergo an aging process. It is assumed that mitochondrial markers of aging are recognized by the mitochondrial quality control system, preventing the accumulation of dysfunctional mitochondria, which normally are subjected to disposal. Possibly, oncocytoma, with its abnormal proliferation of mitochondria occupying the entire cytoplasm, represents the case when segregation of damaged mitochondria is impaired during mitochondrial division. It is plausible that mitochondria contain a "clock" which counts the degree of mitochondrial senescence as the extent of flagging (by ubiquitination) of damaged mitochondria. Mitochondrial aging captures the essence of the systemic aging which must be analyzed. We assume that the mitochondrial aging mechanism is similar to the mechanism of aging of the immune system which we discuss in detail., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Intercellular cross-talk is a fundamental process for spreading cellular signals between neighbouring and distant cells to properly regulate their metabolism, to coordinate homeostasis, adaptation and survival as a functional tissue and organ. In this review, we take a close molecular view of the underpinning molecular mechanisms of such complex intercellular communications. There are several studied forms of cell-to-cell communications considered crucial for the maintenance of multicellular organisms. The most explored is paracrine signalling which is realised through the release of diffusible signalling factors (e.g., hormones or growth factors) from a donor cell and taken up by a recipient cell. More challenging is communication which also does not require the direct contact of cells but is organised through the release of named signalling factors embedded in membranous structures. This mode of cell-to-cell communication is executed through the transfer of extracellular vesicles. Two other types of cellular cross-communication require direct contact of communicating cells. In one type, cells are connected by gap junctions which regulate permeation of chemical signals addressed to a neighbouring cell. Another type of cell communication is organised to provide a cytosolic continuum of adjacent cells joined by different tiny cell membrane extensions coined tunnelling nanotubes. In this review, we consider the various cell communication modes in the heart, and examples of processes in non-cardiac cells which may have mechanistic parallels with cardiovascular cells., (Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

In young rats, ischemic preconditioning (IPC), which consists of 4 cycles of ischemia and reperfusion alleviated kidney injury caused by 40-min ischemia. However,old rats lost their ability to protect the ischemic kidney by IPC. A similar aged phenotype was demonstrated in 6-month-old OXYS rats having signs of premature aging. In the kidney of old and OXYS rats, the levels of acetylated nuclear proteins were higher than in young rats, however, unlike in young rats, acetylation levels in old and OXYS rats were further increased after IPC. In contrast to Wistar rats, age-matched OXYS demonstrated no increase in lysosome abundance and LC3 content in the kidney after ischemia/reperfusion. The kidney LC3 levels were also lower in OXYS, even under basal conditions, and mitochondrial PINK1 and ubiquitin levels were higher, suggesting impaired mitophagy. The kidney mitochondria from old rats contained a population with diminished membrane potential and this fraction was expanded by IPC. Apparently, oxidative changes with aging result in the appearance of malfunctioning renal mitochondria due to a low efficiency of autophagy. Elevated protein acetylation might be a hallmark of aging which is associated with a decreased autophagy, accumulation of dysfunctional mitochondria, and loss of protection against ischemia by IPC.

One of the most important pathological consequences of renal ischemia/reperfusion (I/R) is kidney malfunctioning. I/R leads to oxidative stress, which affects not only nephron cells but also cells of the vascular wall, especially endothelium, resulting in its damage. Assessment of endothelial damage, its role in pathological changes in organ functioning, and approaches to normalization of endothelial and renal functions are vital problems that need to be resolved. The goal of this study was to examine functional and morphological impairments occurring in the endothelium of renal vessels after I/R and to explore the possibility of alleviation of the severity of these changes using mitochondria-targeted antioxidant 10-(6'-plastoquinonyl)decylrhodamine 19 (SkQR1). Here we demonstrate that 40-min ischemia with 10-min reperfusion results in a profound change in the structure of endothelial cells mitochondria, accompanied by vasoconstriction of renal blood vessels, reduced renal blood flow, and increased number of endothelial cells circulating in the blood. Permeability of the kidney vascular wall increased 48 h after I/R. Injection of SkQR1 improves recovery of renal blood flow and reduces vascular resistance of the kidney in the first minutes of reperfusion; it also reduces the severity of renal insufficiency and normalizes permeability of renal endothelium 48 h after I/R. In in vitro experiments, SkQR1 provided protection of endothelial cells from death provoked by oxygen-glucose deprivation. On the other hand, an inhibitor of NO-synthases, L-nitroarginine, abolished the positive effects of SkQR1 on hemodynamics and protection from renal failure. Thus, dysfunction and death of endothelial cells play an important role in the development of reperfusion injury of renal tissues. Our results indicate that the major pathogenic factors in the endothelial damage are oxidative stress and mitochondrial damage within endothelial cells, while mitochondria-targeted antioxidants could be an effective tool for the protection of tissue from negative effects of ischemia.

Aging is associated with a decline of various body functions, including ability to regenerate. Over recent decades, it has been demonstrated that some of these changes could be reversed in response to factors originating from a young organism, for example, fetal stem cells or "young blood" in models of heterochronic parabiosis. Pregnancy might be considered as parabiotic model of the interaction between two organisms of different age. In this work, we analyzed and summarized data on the effects of pregnancy on the maternal organism that confirm the hypothesis that pregnancy rejuvenates the mother's organism or slows its aging.

Previously, we have assembled a cellular model of pyelonephritis which contains a primary culture of renal tubular epithelial cells, mononuclear leukocytes, and bacterial lysate or lipopolysaccharide. After cocultivation of renal cells with leukocytes and bacterial lysate, proinflammatory changes were observed in the renal cells, followed by nitrosative and oxidative stress and cell death. The interaction of bacterial antigens not only with leukocytes, but also with epithelial cells of the renal tubules, was partially mediated by signaling pathways involving Toll-like receptors (TLR2 and TLR4). Activation of these receptors led to increased levels of oxidative stress and synthesis of proinflammatory cytokines (TNF, IL-6, IL-1α) in the renal epithelium, while TLR4 blockade decreased the severity of these processes. Apart from the fact that activation of inflammatory signaling in response to bacterial antigens is observed directly in the renal cells, the presence of leukocytes significantly amplifies the inflammatory response as measured by the level of cytokines generated in the ensemble. In the presence of activated leukocytes, higher expression of TLR2 on the surface of renal cells was observed in response to exposure to bacterial components, which might explain the increased inflammatory response in the presence of leukocytes. The synthesis of IL-1α in the epithelial cells of the renal tubules in this inflammatory model leads to its accumulation in the nuclei, which has been reduced by the TLR4 antagonist polymyxin. TLR2 agonists also led to increased levels of IL-1α. The elevation in the content of IL-1α in nuclei was accompanied by increased acetylation of nuclear proteins, which has been reduced to control values after exposure to protective agents (Trolox, mitochondria-targeted antioxidant SkQR1 or LiCl). The high level of acetylation of histones is probably regulated by proinflammatory cytokines, and to some extent it is a marker of inflammation, which can indirectly be reduced by protective agents.

Background: Limited uncoupling of oxidative phosphorylation is known to be beneficial in various laboratory models of diseases. Linking a triphenyl-phosphonium cation to fluorescein through a decyl (C10) spacer yields a fluorescent uncoupler, coined mitoFluo, that selectively accumulates in energized mitochondria (Denisov et al., Chem.Commun. 2014)., Methods: Proton-transport activity of mitoFluo was tested in liposomes reconstituted with bacteriorhodopsin. To examine the uncoupling action on mitochondria, we monitored mitochondrial membrane potential in parallel with oxygen consumption. Neuro- and nephroprotecting activity was detected by a limb-placing test and a kidney ischemia/reperfusion protocol, respectively., Results: We compared mitoFluo properties with those of its newly synthesized analog having a short (butyl) spacer (C4-mitoFluo). MitoFluo, but not C4-mitoFluo, caused collapse of mitochondrial membrane potential resulting in stimulation of mitochondrial respiration. The dramatic difference in the uncoupling activity of mitoFluo and C4-mitoFluo was in line with the difference in their protonophoric activity on a lipid membrane. The accumulation of mitoFluo in mitochondria was more pronounced than that of C4-mitoFluo. MitoFluo decreased the rate of ROS production in mitochondria. MitoFluo was effective in preventing consequences of brain trauma in rats: it suppressed trauma-induced brain swelling and reduced a neurological deficit. Besides, mitoFluo attenuated acute kidney injury after ischemia/reperfusion in rats., Conclusions: A long alkyl linker was proved mandatory for mitoFluo to be a mitochondria- targeted uncoupler. MitoFluo showed high protective efficacy in certain models of oxidative stress-related diseases., General Significance: MitoFluo is a candidate for developing therapeutic and fluorescence imaging agents to treat brain and kidney pathologies., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The question if mitochondria have some kind of immune system is not trivial. The basis for raising this question is the fact that bacteria, which are progenitors of mitochondria, do have an immune system. The CRISPR system in bacteria based on the principle of RNA interference serves as an organized mechanism for destroying alien nucleic acids, primarily those of viral origin. We have shown that mitochondria are also a target for viral attacks, probably due to a related organization of genomes in these organelles and bacteria. Bioinformatic analysis performed in this study has not given a clear answer if there is a CRISPR-like immune system in mitochondria. However, this does not preclude the possibility of mitochondrial immunity that can be difficult to decipher or that is based on some principles other than those of CRISPR.

Structural organization of mitochondria reflects their functional status and largely is an index of the cell viability. The indirect parameter to assess the functional state of mitochondria and cells is the degree of fragmentation, i. e. a ratio of long or branched mitochondrial structures to rounded mitochondria. The critical need for such evaluations requires the creation of an approach, that allows on the basis of confocal images of mitochondria stained with a fluorescent probe, to create an integral picture of the three-dimensional organization of mitochondria. In the present study, we tested three approaches to analyze the structural architecture of mitochondria under norm and fission induced by oxidative stress. We have revealed that while the most informative way of analysis is a three-dimensional reconstruction based on series of confocal images taken in Z-dimension, however, with some limitations it is plausible to use more simple algorithms of analysis, including that one that uses unitary two-dimensional images. Further improvement of these methods of image analysis will allow more comprehensive analysis of mitochondrial architecture under norm and different pathological states. It may also provide quantification of a number of mitochondrial parameters determining morpho-functional state of mitochondria primarily their absolute and relative volumes and give additional information on three-dimensional organization of mitochondriome.

At first glance, biological differences between male and female sex seem obvious, but, in fact, they affect a vast number of deeper levels apart from reproductive function and related physiological features. Such differences affect all organizational levels including features of cell physiology and even functioning of separate organelles, which, among other things, account for such global processes as resistance to diseases and aging. Understanding of mechanisms underlying resistance of one of the sexes to pathological processes and aging will allow taking into consideration gender differences while developing drugs and therapeutic approaches, and it will provide an opportunity to reproduce and enhance such resistance in the more vulnerable gender. Here we review physiological as well as cellular and biological features of disease course including aging that are affected by gender and discuss potential mechanisms behind these processes. Such mechanisms include features of oxidative metabolism and mitochondrial functioning.

Here, in addition to the previously coined term "mitobiota", we introduce the term "mitodiversity" for various phenotypic and genetic heterogeneities of mitochondria within the same cell or organ. Based on data on the mitochondrial transmembrane potential determined both in situ and in vitro under normal conditions and after organ ischemia/reperfusion, such heterogeneity is most evident under pathologic conditions. Herein, a part of the mitochondrial population with transmembrane potential typical of the normal state is sustained even under a pathological condition that, perhaps, underlies the development of ways of reversing pathology back to the normal state. The membrane potentials of isolated mitochondria were shown to directly correlate with the magnitude of side-scattered light depicting internal structure of mitochondria. We analyzed possible interpretations of data on mitochondrial membrane potential obtained using fluorescent probes. We suggest a possible mechanism underlying retention of fluorescent probes inside the cells and mitochondria.

The recent revival of old theories and setting them on modern scientific rails to a large extent are also relevant to mitochondrial science. Given the widespread belief that mitochondria are symbionts of ancient bacterial origin, the processes inherent to mitochondrial physiology can be revised based on their comparative analysis with possible involvement of bacteria. Such comparison combined with discussion of the role of microbiota in pathogenesis allows discussion of the role of "mitobiota" (we introduce this term) as the combination of different phenotypic manifestations of mitochondria in the organism reflecting pathological changes in the mitochondrial genome. When putting an equal sign between mitochondria and bacteria, we find similarity between the mitochondrial and bacterial theories of cancer. The presence of the term "bacterial infection" suggests "mitochondrial infection", and mitochondrial (oxidative) theory of aging can in some way be transformed into a "bacterial theory of aging". The possible existence of such processes and the data confirming their presence are discussed in this review. If such a comparison has the right to exist, the homeostasis of "mitobiota" is of not lesser physiological importance than homeostasis of microbiota, which has been so intensively discussed recently.

Vascular pathologies pose a significant health problem because of their wide prevalence and high impact on the rate of mortality. Blockade of blood flow in major blood vessels leads to ischaemia associated with oxidative stress, where mitochondria act as a major source of reactive oxygen species (ROS). While low levels of ROS perform a necessary function in normal cellular signalling and metabolism, elevated levels under pathological conditions are detrimental both at the cell and organ level. While cellular oxygenation is necessary to maintain tissue viability, a key pathological occurrence when restoring blood flow to ischaemic tissues is the subsequent burst of ROS generation following reoxygenation, resulting in a cascade of ROS-induced ROS release. This oxygen 'paradox' is a constraint in clinical practice, that is, the need for rapid and maximal restoration of blood flow while at the same time minimising the harmful impact of reperfusion injury on damaged tissues. Mitochondria play a central role in many signalling pathways, including cardioprotection against ischaemic injury and ROS signalling, thus the main target of any anti-ischaemic protective or post-injury therapeutic strategy should include mitochondria. At present, one of the most effective strategies that provide mitochondrial tolerance to ischaemia is ischaemic preconditioning. In addition, pharmacological preconditioning which mimics intrinsic natural protective mechanisms has proven effective at priming biological mechanisms to confront ischaemic damage. This review will discuss the role of mitochondria in contributing to acute ischaemia-reperfusion (IR) injury, and mechanisms of cardioprotection in respect to mitochondrial signalling pathways., (Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

For many decades pharmacological drugs based on lithium salts have been successfully used in psychiatry to treat bipolar disorder, and they remain the "gold standard" of pharmacological therapy of patients with this disease. At the same time, over recent years in experiments in vitro and in vivo a plethora of evidence has accumulated on a positive effect of lithium ions in other areas including their neuro-, cardio-, and nephroprotective properties, regulation of stem cells functions, regulation of inflammation, and others. Numerous studies have shown that the effect of lithium ions involves several mechanisms; however, one of its main targets in the implementation of most of the effects is glycogen synthase kinase 3β, a key enzyme in various pathological and protective signaling pathways in cells. However, one of the main limitations of the use of lithium salts in clinics is their narrow therapeutic window, and the risk of toxic side effects. This review presents the diversity of effects of lithium ions on the organism emphasizing their potential clinical applications with minimal undesirable side effects. In the end, we present a schematic "Lithiometer", comparing the range of Li(+) concentrations that might be used for the treatment of acute pathologies with possible toxic effects of Li(+).

Mitochondrial medicine was established more than 50 years ago after discovery of the very first pathology caused by impaired mitochondria. Since then, more than 100 mitochondrial pathologies have been discovered. However, the number may be significantly higher if we interpret the term "mitochondrial medicine" more widely and include in these pathologies not only those determined by the genetic apparatus of the nucleus and mitochondria, but also acquired mitochondrial defects of non-genetic nature. Now the main problems of mitochondriology arise from methodology, this being due to studies of mitochondrial activities under different models and conditions that are far from the functioning of mitochondria in a cell, organ, or organism. Controversial behavior of mitochondria ("friends and foes") to some extent might be explained by their bacterial origin with possible preservation of "egoistic" features peculiar to bacteria. Apparently, for normal mitochondrial functioning it is essential to maintain homeostasis of a number of mitochondrial elements such as mitochondrial DNA structure, membrane potential, and the system of mitochondrial quality control. Abrogation of these elements can cause a number of pathologies that have become subjects of mitochondrial medicine. Some approaches to therapy of mitochondrial pathologies are discussed.

It is generally accepted that mitochondrial production of reactive oxygen species is nonlinearly related to the value of the mitochondrial membrane potential with significant increment at values exceeding 150 mV. Due to this, high values of the membrane potential are highly dangerous, specifically under pathological conditions associated with oxidative stress. Mild uncoupling of oxidative phosphorylation is an approach to preventing hyperpolarization of the mitochondrial membrane. We confirmed data obtained earlier in our group that dodecylrhodamine 19 (C(12)R1) (a penetrating cation from SkQ family not possessing a plastoquinone group) has uncoupling properties, this fact making it highly potent for use in prevention of pathologies associated with oxidative stress induced by mitochondrial hyperpolarization. Further experiments showed that C(12)R1 provided nephroprotection under ischemia/reperfusion of the kidney as well as under rhabdomyolysis through diminishing of renal dysfunction manifested by elevated level of blood creatinine and urea. Similar nephroprotective properties were observed for low doses (275 nmol/kg) of the conventional uncoupler 2,4-dinitrophenol. Another penetrating cation that did not demonstrate protonophorous activity (SkQR4) had no effect on renal dysfunction. In experiments with induced ischemic stroke, C(12)R1 did not have any effect on the area of ischemic damage, but it significantly lowered neurological deficit. We conclude that beneficial effects of penetrating cation derivatives of rhodamine 19 in renal pathologies and brain ischemia may be at least partially explained by uncoupling of oxidation and phosphorylation.

Programmed execution of various cells and intracellular structures is hypothesized to be not the only example of elimination of biological systems - the general mechanism can also involve programmed execution of organs and organisms. Modern rating of programmed cell death mechanisms includes 13 mechanistic types. As for some types, the mechanism of actuation and manifestation of cell execution has been basically elucidated, while the causes and intermediate steps of the process of fatal failure of organs and organisms remain unknown. The analysis of deaths resulting from a sudden heart arrest or multiple organ failure and other acute and chronic pathologies leads to the conclusion of a special role of mitochondria and oxidative stress activating the immune system. Possible mechanisms of mitochondria-mediated induction of the signaling cascades involved in organ failure and death of the organism are discussed. These mechanisms include generation of reactive oxygen species and damage-associated molecular patterns in mitochondria. Some examples of renal failure-induced deaths are presented with mechanisms and settings determined by some hypothetical super system rather than by the kidneys themselves. This system plays the key role in the process of physiological senescence and termination of an organism. The facts presented suggest that it is the immune system involved in mitochondrial signaling that can act as the system responsible for the organism's death.

The influence of the mitochondria-targeted antioxidant SkQR1 on gentamycin-induced nephrotoxicity and ototoxicity has been analyzed. SkQR1 reduces the death of kidney epithelium cells and decreases the severity of renal failure caused by gentamycin application and also lowers the animals' mortality. Treatment with SkQR1 also decreases gentamycin-induced hearing loss. Mitochondria-targeted antioxidants, such as SkQR1, are new promising agents for preventing negative consequences of therapy with antibiotics.

Oxidative stress-related renal pathologies apparently include rhabdomyolysis and ischemia/reperfusion phenomenon. These two pathologies were chosen for study in order to develop a proper strategy for protection of the kidney. Mitochondria were found to be a key player in these pathologies, being both the source and the target for excessive production of reactive oxygen species (ROS). A mitochondria-targeted compound which is a conjugate of a positively charged rhodamine molecule with plastoquinone (SkQR1) was found to rescue the kidney from the deleterious effect of both pathologies. Intraperitoneal injection of SkQR1 before the onset of pathology not only normalized the level of ROS and lipid peroxidized products in kidney mitochondria but also decreased the level of cytochrome c in the blood, restored normal renal excretory function and significantly lowered mortality among animals having a single kidney exposed to ischemia/reperfusion. The SkQR1-derivative missing plastoquinone (C12R1) possessed some, although limited nephroprotective properties and enhanced animal survival after ischemia/reperfusion. SkQR1 was found to induce some elements of nephroprotective pathways providing ischemic tolerance such as an increase in erythropoietin levels and phosphorylation of glycogen synthase kinase 3β in the kidney. SkQR1 also normalized renal erythropoietin level lowered after kidney ischemia/reperfusion and injection of a well-known nephrotoxic agent gentamicin., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A mitochondria-targeted chimeric compound consisting of a rhodamine derivative linked to a plastoquinone molecule (10-(6'-plastoquinonyl)decylrhodamine, SkQR1) was studied under conditions of acute brain or kidney damage. A protective effect of this compound was demonstrated in a model of focal brain ischemia, rat kidney ischemia/reperfusion, myoglobinuria (rhabdomyolysis, or crush syndrome), and pyelonephritis. We found that a single intraperitoneal injection of SkQR1 diminishes the size of the ischemic zone in the brain and improves performance of a test characterizing neurological deficit in ischemic animals. Control substance not containing plastoquinone appeared to be not neuroprotective. The data show that SkQR1 is a nephroprotectant and neuroprotectant, which can be due to the antioxidative action of this Skulachev cation.