Mitochondrion-targeted antioxidant SkQ1 prevents rapid animal death caused by highly diverse shocks.

The response to stress involves the activation of pathways leading either to protection from the stress origin, eventually resulting in development of stress resistance, or activation of the rapid death of the organism. Here we hypothesize that mitochondrial reactive oxygen species (mtROS) play a key role in stress-induced programmed death of the organism, which we called "phenoptosis" in 1997. We demonstrate that the synthetic mitochondria-targeted antioxidant SkQ1 (which specifically abolishes mtROS) prevents rapid death of mice caused by four mechanistically very different shocks: (a) bacterial lipopolysaccharide (LPS) shock, (b) shock in response to intravenous mitochondrial injection, (c) cold shock, and (d) toxic shock caused by the penetrating cation C12TPP. Importantly, under all these stresses mortality was associated with a strong elevation of the levels of pro-inflammatory cytokines and administration of SkQ1 was able to switch off the cytokine storms. Since the main effect of SkQ1 is the neutralization of mtROS, this study provides evidence for the role of mtROS in the activation of innate immune responses mediating stress-induced death of the organism. We propose that SkQ1 may be used clinically to support patients in critical conditions, such as septic shock, extensive trauma, cooling, and severe infection by bacteria or viruses.

NETosis: Molecular Mechanisms, Role in Physiology and Pathology.

NETosis is a program for formation of neutrophil extracellular traps (NETs), which consist of modified chromatin decorated with bactericidal proteins from granules and cytoplasm. Various pathogens, antibodies and immune complexes, cytokines, microcrystals, and other physiological stimuli can cause NETosis. Induction of NETosis depends on reactive oxygen species (ROS), the main source of which is NADPH oxidase. Activation of NADPH oxidase depends on increase in the concentration of Ca2+ in the cytoplasm and in some cases on the generation of ROS in mitochondria. NETosis includes release of the granule components into the cytosol, modification of histones leading to chromatin decondensation, destruction of the nuclear envelope, as well as formation of pores in the plasma membrane. In this review, basic mechanisms of NETosis, as well as its role in the pathogenesis of some diseases including COVID-19 are discussed.

Mitochondrial Transplantation: A Critical Analysis.

"Mitochondrial transplantation" refers to a procedure for introducing isolated mitochondria into a damaged area of a heart or other organ. A considerable amount of data has been accumulated on the therapeutic effects of "mitochondrial transplantation" in animals with ischemic heart damage. In 2017, the first attempts were made to apply this procedure in a clinic. The authors of the method suggest that exogenous mitochondria penetrate into cardiomyocytes, retaining functional activity, and compensate for impaired energy output of endogenous mitochondria. This hypothesis contradicts the well-known fact of loss of mitochondrial functions in the presence of high concentrations of Ca2+, which are characteristic of the extracellular medium. This review critically considers the possible mechanisms of the therapeutic effect of "mitochondrial transplantation".

Mitoptosis, Twenty Years After.

In 1999 V. P. Skulachev proposed the term "mitoptosis" to refer to the programmed elimination of mitochondria in living cells. According to the initial thought, mitoptosis serves to protect cells from malfunctioning of the damaged mitochondria. At the same time, a new mechanism of the complete mitochondria elimination was found under the conditions of massive mitochondrial damage associated with oxidative stress. In this experimental model, mitochondrial cluster formation in the perinuclear region leads to the formation of "mitoptotic body" surrounded by a single-layer membrane and subsequent release of mitochondria from the cell. Later, it was found that mitoptosis plays an important role in various normal and pathological processes that are not necessarily associated with the mitochondrial damage. It was found that mitoptosis takes place during cell differentiation, self-maintenance of hematopoietic stem cells, metabolic remodelling, and elimination of the paternal mitochondria in organisms with the maternal inheritance of the mitochondrial DNA. Moreover, the associated with mitoptosis release of mitochondrial components into the blood may be involved in the transmission of signals between cells, but also leads to the development of inflammatory and autoimmune diseases. Mitoptosis can be attributed to the asymmetric inheritance of mitochondria in the division of yeast and some animal cells, when the defective mitochondria are transferred to one of the newly formed cells. Finally, a specific form of mitoptosis appears to be selective elimination of mitochondria with deleterious mutations in whole follicular ovarian cells in mammals. During formation of the primary follicle, the mitochondrial DNA copy number is significantly reduced. After division, the cells that receive predominantly mitochondria with deleterious mutations in their mtDNA die, thereby reducing the likelihood of transmission of these mutations to offspring. Further study of the mechanisms of mitoptosis in normal and pathological conditions is important both for understanding the processes of development and aging, and for designing therapeutic approaches for inflammatory, neurodegenerative and other diseases.

COVID-19 and Oxidative Stress.

Pathogenesis of the novel coronavirus infection COVID-19 is the subject of active research around the world. COVID-19 caused by the SARS-CoV-2 is a complex disease in which interaction of the virus with target cells, action of the immune system and the body's systemic response to these events are closely intertwined. Many respiratory viral infections, including COVID-19, cause death of the infected cells, activation of innate immune response, and secretion of inflammatory cytokines. All these processes are associated with the development of oxidative stress, which makes an important contribution to pathogenesis of the viral infections. This review analyzes information on the oxidative stress associated with the infections caused by SARS-CoV-2 and other respiratory viruses. The review also focuses on involvement of the vascular endothelium in the COVID-19 pathogenesis.

Molecular Dynamics Modeling of the Interaction of Cationic Fluorescent Lipid Peroxidation-Sensitive Probes with the Mitochondrial Membrane.

Cardiolipin (CL) plays a central role in lipid peroxidation (LPO) of the mitochondrial inner membrane due to higher content of unsaturated fatty acids in CL in comparison with the other phospholipids. CL oxidation plays an important role in the regulation of various intracellular signaling pathways and its excessive oxidation contributes to the development of various pathologies and, possibly, participates in the aging process. Mitochondria-targeted antioxidants containing triphenylphosphonium (TPP+) effectively protect CL from oxidation. It is assumed that fluorescent probes on the basis of the C11-BODIPY fluorophore sensitive to LPO and containing TPP+ can selectively register CL oxidation. To test this possibility, we carried out a molecular dynamic simulation of such probes in a model mitochondrial membrane. It is shown that the probes are located in the membrane at the same depth as the unsaturated bonds in CL molecules sensitive to oxidation. Increasing the length of the linker that binds the fluorophore and TPP+ residue ha little effect on the position of the probe in the membrane. This indicates the possibility of modifying the linker to increase the selectivity of the probes to CL.

Does Oxidation of Mitochondrial Cardiolipin Trigger a Chain of Antiapoptotic Reactions?

Oxidative stress causes selective oxidation of cardiolipin (CL), a four-tail lipid specific for the inner mitochondrial membrane. Interaction with oxidized CL transforms cytochrome c into peroxidase capable of oxidizing even more CL molecules. Ultimately, this chain of events leads to the pore formation in the outer mitochondrial membrane and release of mitochondrial proteins, including cytochrome c, into the cytoplasm. In the cytoplasm, cytochrome c promotes apoptosome assembly that triggers apoptosis (programmed cell death). Because of this amplification cascade, even an occasional oxidation of a single CL molecule by endogenously formed reactive oxygen species (ROS) might cause cell death, unless the same CL oxidation triggers a separate chain of antiapoptotic reactions that would prevent the CL-mediated apoptotic cascade. Here, we argue that the key function of CL in mitochondria and other coupling membranes is to prevent proton leak along the interface of interacting membrane proteins. Therefore, CL oxidation should increase proton permeability through the CL-rich clusters of membrane proteins (CL islands) and cause a drop in the mitochondrial membrane potential (MMP). On one hand, the MMP drop should hinder ROS generation and further CL oxidation in the entire mitochondrion. On the other hand, it is known to cause rapid fission of the mitochondrial network and formation of many small mitochondria, only some of which would contain oxidized CL islands. The fission of mitochondrial network would hinder apoptosome formation by preventing cytochrome c release from healthy mitochondria, so that slowly working protein quality control mechanisms would have enough time to eliminate mitochondria with the oxidized CL. Because of these two oppositely directed regulatory pathways, both triggered by CL oxidation, the fate of the cell appears to be determined by the balance between the CL-mediated proapoptotic and antiapoptotic reactions. Since this balance depends on the extent of CL oxidation, mitochondria-targeted antioxidants might be able to ensure cell survival in many pathologies by preventing CL oxidation.

Mitochondria-Targeted Antioxidant SkQ1 (10-(6´-Plastoquinonyl)decyltriphenylphosphonium Bromide) Inhibits Mast Cell Degranulation in vivo and in vitro.

The therapeutic effect of mitochondria-targeted antioxidant 10-(6´-plastoquinonyl)decyltriphenylphosphonium bromide (SkQ1) in experimental models of acute inflammation and wound repair has been shown earlier. It was suggested that the antiinflammatory activity of SkQ1 is related to its ability to suppress inflammatory activation of the vascular endothelium and neutrophil migration into tissues. Here, we demonstrated that SkQ1 inhibits activation of mast cells (MCs) followed by their degranulation and histamine release in vivo and in vitro. Intraperitoneal injections of SkQ1 in the mouse air-pouch model reduced the number of leukocytes in the air-pouch cavity and significantly decreased the histamine content in it, as well as suppressing MC degranulation in the air-pouch tissue. The direct effect of SkQ1 on MCs was studied in vitro in the rat basophilic leukemia RBL-2H3 cell line. SkQ1 inhibited induced degranulation of RBL-2H3 cells. These results suggest that mitochondrial reactive oxygen species are involved in the activation of MCs. It is known that MCs play a crucial role in regulation of vascular permeability by secreting histamine. Suppression of MC degranulation by SkQ1 might be a significant factor in the antiinflammatory activity of this mitochondria-targeted antioxidant.

Mitochondria-Targeted Antioxidant SkQR1 Reduces TNF-Induced Endothelial Permeability in vitro.

Prolonged or excessive increase in the circulatory level of proinflammatory tumor necrosis factor (TNF) leads to abnormal activation and subsequent damage to endothelium. TNF at high concentrations causes apoptosis of endothelial cells. Previously, using mitochondria-targeted antioxidants of SkQ family, we have shown that apoptosis of endothelial cells is dependent on the production of reactive oxygen species (ROS) in mitochondria (mito-ROS). Now we have found that TNF at low concentrations does not cause cell death but activates caspase-3 and caspase-dependent increase in endothelial permeability in vitro. This effect is probably due to the cleavage of ß-catenin - an adherent junction protein localized in the cytoplasm. We have also shown that extracellular matrix metalloprotease 9 (MMP9) VE-cadherin shedding plays a major role in the TNF-induced endothelial permeability. The mechanisms of the caspase-3 and MMP9 activation are probably not related to each other since caspase inhibition did not affect VE-cadherin cleavage and MMP9 inhibition had no effect on the caspase-3 activation. Mitochondria-targeted antioxidant SkQR1 inhibited TNF-induced increase in endothelial permeability. SkQR1 also inhibited caspase-3 activation, ß-catenin cleavage, and MMP9-dependent VE-cadherin shedding. The data suggest that mito-ROS are involved in the increase in endothelial permeability due to the activation of both caspase-dependent cleavage of intracellular proteins and of MMP9-dependent cleavage of the transmembrane cell-to-cell contact proteins.

Role of Reactive Oxygen Species in Mast Cell Degranulation.

Mast cells are a heterogeneous multifunctional cellular population that promotes connective tissue homeostasis by slow release of biologically active substances, affecting primarily the permeability of vessels and vascular tone, maintenance of electrolyte and water balance, and composition of the extracellular matrix. Along with this, they can rapidly release inflammatory mediators and chemotactic factors that ensure the mobilization of effector innate immune cells to fight against a variety of pathogens. Furthermore, they play a key role in initiation of allergic reactions. Aggregation of high affinity receptors to IgE (FcεRI) results in rapid degranulation and release of inflammatory mediators. It is known that reactive oxygen species (ROS) participate in intracellular signaling and, in particular, stimulate production of several proinflammatory cytokines that regulate the innate immune response. In this review, we focus on known molecular mechanisms of FcεRI-dependent activation of mast cells and discuss the role of ROS in the regulation of this pathway.

Low Concentrations of Uncouplers of Oxidative Phosphorylation Prevent Inflammatory Activation of Endothelial Cells by Tumor Necrosis Factor.

In endothelial cells, mitochondria play an important regulatory role in physiology as well as in pathophysiology related to excessive inflammation. We have studied the effect of low doses of mitochondrial uncouplers on inflammatory activation of endothelial cells using the classic uncouplers 2,4-dinitrophenol and 4,5,6,7-tetrachloro-2-trifluoromethylbenzimidazole, as well as the mitochondria-targeted cationic uncoupler dodecyltriphenylphosphonium (C12TPP). All of these uncouplers suppressed the expression of E-selectin, adhesion molecules ICAM1 and VCAM1, as well as the adhesion of neutrophils to endothelium induced by tumor necrosis factor (TNF). The antiinflammatory action of the uncouplers was at least partially mediated by the inhibition of NFκB activation due to a decrease in phosphorylation of the inhibitory subunit IκBα. The dynamic concentration range for the inhibition of ICAM1 expression by C12TPP was three orders of magnitude higher compared to the classic uncouplers. Probably, the decrease in membrane potential inhibited the accumulation of penetrating cations into mitochondria, thus lowering the uncoupling activity and preventing further loss of mitochondrial potential. Membrane potential recovery after the removal of the uncouplers did not abolish its antiinflammatory action. Thus, mild uncoupling could induce TNF resistance in endothelial cells. We found no significant stimulation of mitochondrial biogenesis or autophagy by the uncouplers. However, we observed a decrease in the relative amount of fragmented mitochondria. The latter may significantly change the signaling properties of mitochondria. Earlier we showed that both classic and mitochondria-targeted antioxidants inhibited the TNF-induced NFκB-dependent activation of endothelium. The present data suggest that the antiinflammatory effect of mild uncoupling is related to its antioxidant action.

Mitochondria-targeted antioxidants prevent TNFα-induced endothelial cell damage.

Increased serum level of tumor necrosis factor α (TNFα) causes endothelial dysfunction and leads to serious vascular pathologies. TNFα signaling is known to involve reactive oxygen species (ROS). Using mitochondria-targeted antioxidant SkQR1, we studied the role of mitochondrial ROS in TNFα-induced apoptosis of human endothelial cell line EAhy926. We found that 0.2 nM SkQR1 prevents TNFα-induced apoptosis. SkQR1 has no influence on TNFα-dependent proteolytic activation of caspase-8 and Bid, but it inhibits cytochrome c release from mitochondria and cleavage of caspase-3 and its substrate PARP. SkQ analogs lacking the antioxidant moieties do not prevent TNFα-induced apoptosis. The antiapoptotic action of SkQR1 may be related to other observations made in these experiments, namely SkQR1-induced increase in Bcl-2 and corresponding decrease in Bax as well as p53. These results indicate that mitochondrial ROS production is involved in TNFα-initiated endothelial cell death, and they suggest the potential of mitochondria-targeted antioxidants as vasoprotectors.

The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III.

A mechanism for the induction of programmed cell death (apoptosis) upon dysfunction of the mitochondrial respiratory chain has been studied. Previously, we had found that inhibition of mitochondrial cytochrome bc1, a component of the electron transport chain complex III, leads to activation of tumor suppressor p53, followed by apoptosis induction. The mitochondrial respiratory chain is coupled to the de novo pyrimidine biosynthesis pathway via the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). The p53 activation induced in response to the inhibition of the electron transport chain complex III has been shown to be triggered by the impairment of the de novo pyrimidine biosynthesis due to the suppression of DHODH. However, it remained unclear whether the suppression of the DHODH function is the main cause of the observed apoptotic cell death. Here, we show that apoptosis in human colon carcinoma cells induced by the mitochondrial respiratory chain complex III inhibition can be prevented by supplementation with uridine or orotate (products of the reaction catalyzed by DHODH) rather than with dihydroorotate (a DHODH substrate). We conclude that apoptosis is induced in response to the impairment of the de novo pyrimidine biosynthesis caused by the inhibition of DHODH. The conclusion is supported by the experiment showing that downregulation of DHODH by RNA interference leads to accumulation of the p53 tumor suppressor and to apoptotic cell death.

[Mitochondria-targeted antioxidant SkQR1 selectively protects MDR-negative cells against ionizing radiation].

Radioprotection appeared to be an important problem of today due to atom energetic development and utilization of radiation material in the industry, science and medicine. It has been shown that mitochondrial targeted antioxidant SkQR1 could attenuate radiation injury of human erythroleukemia K562 cells. Pretreatment with SkQR1 before irradiation decreased DNA double strand breaks formation, diminished the number of chromosomal aberrations and suppressed delayed ROS production. Prevention of oxidative stress and normalization of mitochondrial function by mitochondria-targeted antioxidants may be a potential therapeutic strategy not only against immediate consequences of radiation, but, either against its late consequences such as genomic instability. SkQR1 did not protect against radiation-induced damage the K562 subline with high level of multidrug resistance (MDR) due to SkQR1 extrusion with Pgp 170 MDR pump. We suggest that mitochondria-targeted antioxidants might be used for selective protection of normal cells against radiation-induced damage without interference with radiotherapy of MDR-positive tumors.

SkBQ - prooxidant addressed to mitochondria.

Oxidative stress and mitochondrial dysfunction are the key links in the chain of development of pathologies associated with the violation of cellular energy metabolism. Development of mitochondria-addressed compounds highly specific for chemical processes is one of the most promising ways to develop approaches to the treatment of inherited and age-related diseases with mitochondrial etiology. Correlation of structure and chemical activity of the test compounds from a class of lipophilic cations revealed the key role of substituents in the aromatic ring of 1,4-benzoquinones in the manifestation of high antioxidant properties. In this work, it is shown that a synthesized benzoquinone derivative conjugated in position 6 with membrane-penetrating cation of decyltriphenylphosphonium and with substituents at position 2, 3, and 5 (SkBQ) has much lower antioxidant and significantly higher prooxidant activity in comparison with similar derivatives of plasto- and toluquinone SkQ1 and SkQT1 in experiments on isolated mitochondria. At the same time, SkBQ, like SkQ1 and SkQT1, can be reduced by the respiratory chain in the center i of complex III and decrease the mitochondrial membrane potential. In cell cultures of human fibroblasts, it was revealed that SkBQ does not protect cells from apoptosis induced by hydrogen peroxide. Under the same conditions, SkQ1 and SkQT1 exhibit a powerful protective effect. Thus, SkBQ can be seen as a mitochondria-addressed prooxidant. The possibility of using SkBQ as an anticancer drug for the treatment of cancers such as prostate cancer whose cells are sensitive to mitochondrial reactive oxygen species is discussed.

Novel mitochondria-targeted compounds composed of natural constituents: conjugates of plant alkaloids berberine and palmatine with plastoquinone.

Novel mitochondria-targeted compounds composed entirely of natural constituents have been synthesized and tested in model lipid membranes, in isolated mitochondria, and in living human cells in culture. Berberine and palmatine, penetrating cations of plant origin, were conjugated by nonyloxycarbonylmethyl residue with the plant electron carrier and antioxidant plastoquinone. These conjugates (SkQBerb, SkQPalm) and their analogs lacking the plastoquinol moiety (C10Berb and C10Palm) penetrated across planar bilayer phospholipid membrane in their cationic forms and accumulated in isolated mitochondria or in mitochondria in living human cells in culture. Reduced forms of SkQBerb and SkQPalm inhibited lipid peroxidation in isolated mitochondria at nanomolar concentrations. In isolated mitochondria and in living cells, the berberine and palmatine moieties were not reduced, so antioxidant activity belonged exclusively to the plastoquinol moiety. In human fibroblasts, nanomolar SkQBerb and SkQPalm prevented fragmentation of mitochondria and apoptosis induced by exogenous hydrogen peroxide. At higher concentrations, conjugates of berberine and palmatine induced proton transport mediated by free fatty acids both in model and in mitochondrial membrane. In mitochondria this process was facilitated by the adenine nucleotide carrier. As an example of application of the novel mitochondria-targeted antioxidants SkQBerb and SkQPalm to studies of signal transduction, we discuss induction of cell cycle arrest, differentiation, and morphological normalization of some tumor cells. We suggest that production of oxygen radicals in mitochondria is necessary for growth factors-MAP-kinase signaling, which supports proliferation and transformed phenotype.

Mitochondrial-targeted plastoquinone derivatives. Effect on senescence and acute age-related pathologies.

Plastoquinone, a very effective electron carrier and antioxidant of chloroplasts, was conjugated with decyltriphenylphosphonium to obtain a cation easily penetrating through membranes. This cation, called SkQ1, is specifically targeted to mitochondria by electrophoresis in the electric field formed by the mitochondrial respiratory chain. The respiratory chain also regenerates reduced SkQ1H(2) from its oxidized form that appears as a result of the antioxidant activity of SkQ1H(2). SkQ1H(2) prevents oxidation of cardiolipin, a mitochondrial phospholipid that is especially sensitive to attack by reactive oxygen species (ROS). In cell cultures, SkQ1 and its analog plastoquinonyl decylrhodamine 19 (SkQR1) arrest H(2)O(2)-induced apoptosis. When tested in vivo, SkQs (i) prolong the lifespan of fungi, crustaceans, insects, fish, and mice, (ii) suppress appearance of a large number of traits typical for age-related senescence (cataract, retinopathies, achromotrichia, osteoporosis, lordokyphosis, decline of the immune system, myeloid shift of blood cells, activation of apoptosis, induction of ß-galactosidase, phosphorylation of H2AX histones, etc.) and (iii) lower tissue damage and save the lives of young animals after treatments resulting in kidney ischemia, rhabdomyolysis, heart attack, arrhythmia, and stroke. We suggest that the SkQs reduce mitochondrial ROS and, as a consequence, inhibit mitochondria-mediated apoptosis, an obligatory step of execution of programs responsible for both senescence and fast "biochemical suicide" of an organism after a severe metabolic crisis.

Reactive oxygen species produced in mitochondria are involved in age-dependent changes of hematopoietic and mesenchymal progenitor cells in mice. A study with the novel mitochondria-targeted antioxidant SkQ1.

Lifelong treatment of mice with the effective mitochondria-targeted antioxidant SkQ1 [10-(6'-plastoquinonyl) decyltriphenylphosphonium] does not affect hematopoietic stem cells (HSC) and more differentiated hematopoietic progenitors but significantly decelerates age-dependent changes in peripheral blood. During the first 13 months, SkQ1 (0.9 or 28.8 nmol/kg day) prevents age-dependent myeloid shift (increase in the proportion of granulocytes and decrease in the proportion of lymphocytes). During the next year of treatment the effect disappears, and the hemogram of 2-year-old treated mice does not differ from the control. The number of mesenchymal stem cells (MSC) in the bone marrow does not change during 2 years of treatment with SkQ1, but the concentration of MSC progeny fibroblast colony-forming units (CFU-F) increases with dose of SkQ1. The concentration of CFU-F after 1 and 2 years treatment with SkQ1 is twice higher than in young mice. Our data indicate that the stromal environment of hematopoietic cells could be the primary target of age-dependent changes mediated by reactive oxygen species produced in mitochondria. The anti-aging effects of SkQ1 described here are in perfect agreement with the inhibitory effects of this antioxidant on aging observed in the other models.

Mitochondria as source of reactive oxygen species under oxidative stress. Study with novel mitochondria-targeted antioxidants--the "Skulachev-ion" derivatives.

Production of reactive oxygen species (ROS) in mitochondria was studied using the novel mitochondria-targeted antioxidants (SkQ) in cultures of human cells. It was shown that SkQ rapidly (1-2 h) and selectively accumulated in mitochondria and prevented oxidation of mitochondrial components under oxidative stress induced by hydrogen peroxide. At nanomolar concentrations, SkQ inhibited oxidation of glutathione, fragmentation of mitochondria, and translocation of Bax from cytosol into mitochondria. The last effect could be related to prevention of conformational change in the adenine nucleotide transporter, which depends on oxidation of critical thiols. Mitochondria-targeted antioxidants at nanomolar concentrations prevented accumulation of ROS and cell death under oxidative stress. These effects required 24 h or more (depending on the cell type) preincubation, and this was not related to slow induction of endogenous antioxidant systems. It is suggested that SkQ slowly accumulates in a small subpopulation of mitochondria that have decreased membrane potential and produce the major part of ROS under oxidative stress. This population was visualized in the cells using potential-sensitive dye. The possible role of the small fraction of "bad" mitochondria in cell physiology is discussed.

Novel mitochondria-targeted antioxidants, "Skulachev-ion" derivatives, accelerate dermal wound healing in animals.

It is shown that the novel mitochondria-targeted antioxidant SkQ1, (10-(6'-plastoquinonyl) decyltriphenylphosphonium) stimulates healing of full-thickness dermal wounds in mice and rats. Treatment with nanomolar doses of SkQ1 in various formulations accelerated wound cleaning and suppressed neutrophil infiltration at the early (7 h) steps of inflammatory phase. SkQ1 stimulated formation of granulation tissue and increased the content of myofibroblasts in the beginning of regenerative phase of wound healing. Later this effect caused accumulation of collagen fibers. Local treatment with SkQ1 stimulated re-epithelization of the wound. Lifelong treatment of mice with SkQ1 supplemented with drinking water strongly stimulated skin wounds healing in old (28 months) animals. In an in vitro model of wound in human cell cultures, SkQ1 stimulated movement of epitheliocytes and fibroblasts into the "wound". Myofibroblast differentiation of subcutaneous fibroblasts was stimulated by SkQ1. It is suggested that SkQ1 stimulates wound healing by suppression of the negative effects of oxidative stress in the wound and also by induction of differentiation. Restoration of regenerative processes in old animals is consistent with the "rejuvenation" effects of SkQ1, which prevents some gerontological diseases.