Publications by authors named "Vladimir P Skulachev"

89 Publications

Alternative Animal Models of Aging Research.

Front Mol Biosci 2021 17;8:660959. Epub 2021 May 17.

Computational Biology Group, Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.

Most research on mechanisms of aging is being conducted in a very limited number of classical model species, i.e., laboratory mouse (), rat (), the common fruit fly () and roundworm (). The obvious advantages of using these models are access to resources such as strains with known genetic properties, high-quality genomic and transcriptomic sequencing data, versatile experimental manipulation capabilities including well-established genome editing tools, as well as extensive experience in husbandry. However, this approach may introduce interpretation biases due to the specific characteristics of the investigated species, which may lead to inappropriate, or even false, generalization. For example, it is still unclear to what extent knowledge of aging mechanisms gained in short-lived model organisms is transferable to long-lived species such as humans. In addition, other specific adaptations favoring a long and healthy life from the immense evolutionary toolbox may be entirely missed. In this review, we summarize the specific characteristics of emerging animal models that have attracted the attention of gerontologists, we provide an overview of the available data and resources related to these models, and we summarize important insights gained from them in recent years. The models presented include short-lived ones such as killifish (), long-lived ones such as primates (), bathyergid mole-rats (), bats (), birds, olms (), turtles, greenland sharks, bivalves ), and potentially non-aging ones such as and .
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http://dx.doi.org/10.3389/fmolb.2021.660959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166319PMC
May 2021

A Crosstalk between the Biorhythms and Gatekeepers of Longevity: Dual Role of Glycogen Synthase Kinase-3.

Biochemistry (Mosc) 2021 Apr;86(4):433-448

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.

This review discusses genetic and molecular pathways that link circadian timing with metabolism, resulting in the emergence of positive and negative regulatory feedback loops. The Nrf2 pathway is believed to be a component of the anti-aging program responsible for the healthspan and longevity. Nrf2 enables stress adaptation by activating cell antioxidant defense and other metabolic processes via control of expression of over 200 target genes in response to various types of stress. The GSK3 system represents a "regulating valve" that controls fine oscillations in the Nrf2 level, unlike Keap1, which prevents significant changes in the Nrf2 content in the absence of oxidative stress and which is inactivated by the oxidative stress. Furthermore, GSK3 modifies core circadian clock proteins (Bmal1, Clock, Per, Cry, and Rev-erbα). Phosphorylation by GSK3 leads to the inactivation and degradation of circadian rhythm-activating proteins (Bmal1 and Clock) and vice versa to the activation and nuclear translocation of proteins suppressing circadian rhythms (Per and Rev-erbα) with the exception of Cry protein, which is likely to be implicated in the fine tuning of biological clock. Functionally, GSK3 appears to be one of the hubs in the cross-regulation of circadian rhythms and antioxidant defense. Here, we present the data on the crosstalk between the most powerful cell antioxidant mechanism, the Nrf2 system, and the biorhythm-regulating system in mammals, including the impact of GSK3 overexpression and knockout on the Nrf2 signaling. Understanding the interactions between the regulatory cascades linking homeostasis maintenance and cell response to oxidative stress will help in elucidating molecular mechanisms that underlie aging and longevity.
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http://dx.doi.org/10.1134/S0006297921040052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033555PMC
April 2021

Mitochondria-targeted 1,4-naphthoquinone (SkQN) is a powerful prooxidant and cytotoxic agent.

Biochim Biophys Acta Bioenerg 2020 08 17;1861(8):148210. Epub 2020 Apr 17.

A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Russian Federation. Electronic address:

An increase in the production of reactive oxygen species (ROS) in mitochondria due to targeted delivery of redox active compounds may be useful in studies of modulation of cell functions by mitochondrial ROS. Recently, the mitochondria-targeted derivative of menadione (MitoK) was synthesized. However, MitoK did not induce mitochondrial ROS production and lipid peroxidation while exerting significant cytotoxic action. Here we synthesized 1,4-naphthoquinone conjugated with alkyltriphenylphosphonium (SkQN) as a prototype of mitochondria-targeted prooxidant, and its redox properties, interactions with isolated mitochondria, yeast cells and various human cell lines were investigated. According to electrochemical measurements, SkQN was more active redox agent and, due to the absence of methyl group in the naphthoquinone ring, more reactive as electrophile than MitoK. SkQN (but not MitoK) stimulated hydrogen peroxide production in isolated mitochondria. At low concentrations, SkQN stimulated state 4 respiration in mitochondria, decreased membrane potential, and blocked ATP synthesis, being more efficient uncoupler of oxidative phosphorylation than MitoK. In yeast cells, SkQN decreased cell viability and induced oxidative stress and mitochondrial fragmentation. SkQN killed various tumor cells much more efficiently than MitoK. Since many tumors are characterized by increased oxidative stress, the use of new mitochondria-targeted prooxidants may be a promising strategy for anticancer therapy.
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http://dx.doi.org/10.1016/j.bbabio.2020.148210DOI Listing
August 2020

Perspectives of lifespan extension: focus on external or internal resources?

Aging (Albany NY) 2020 03 27;12(6):5566-5584. Epub 2020 Mar 27.

Faculty of Mechanics and Mathematics, Lomonosov Moscow State University, Moscow 119991, Russia.

and naked mole rats () are vivid examples of social mammals that differ from their relatives in particular by an increased lifespan and a large number of neotenic features. An important fact for biogerontology is that the mortality rate of (a maximal lifespan of more than 32 years, which is very large for such a small rodent) negligibly grows with age. The same is true for modern people in developed countries below the age of 60. It is important that the juvenilization of traits that separate humans from chimpanzees evolved over thousands of generations and millions of years. Rapid advances in technology resulted in a sharp increase in the life expectancy of human beings during the past 100 years. Currently, the human life expectancy has exceeded 80 years in developed countries. It cannot be excluded that the potential for increasing life expectancy by an improvement in living conditions will be exhausted after a certain period of time. New types of geroprotectors should be developed that protect not only from chronic phenoptosis gradual poisoning of the body with reactive oxygen species (ROS) but also from acute phenoptosis, where strong increase in the level of ROS immediately kills an already aged individual. Geroprotectors might be another anti-aging strategy along with neoteny (a natural physiological phenomenon) and technical progress.
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http://dx.doi.org/10.18632/aging.102981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138562PMC
March 2020

Mitochondria in the Nuclei of Rat Myocardial Cells.

Cells 2020 03 14;9(3). Epub 2020 Mar 14.

A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia.

Electron microscopic study of cardiomyocytes taken from healthy Wistar and OXYS rats and naked mole rats () revealed mitochondria in nuclei that lacked part of the nuclear envelope. The direct interaction of mitochondria with nucleoplasm is shown. The statistical analysis of the occurrence of mitochondria in cardiomyocyte nuclei showed that the percentage of nuclei with mitochondria was roughly around 1%, and did not show age and species dependency. Confocal microscopy of normal rat cardiac myocytes revealed a branched mitochondrial network in the vicinity of nuclei with an organization different than that of interfibrillar mitochondria. This mitochondrial network was energetically functional because it carried the membrane potential that responded by oscillatory mode after photodynamic challenge. We suggest that the presence of functional mitochondria in the nucleus is not only a consequence of certain pathologies but rather represents a normal biological phenomenon involved in mitochondrial/nuclear interactions.
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http://dx.doi.org/10.3390/cells9030712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140638PMC
March 2020

Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program.

Proc Natl Acad Sci U S A 2020 03 9;117(12):6491-6501. Epub 2020 Mar 9.

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia;

The mitochondria of various tissues from mice, naked mole rats (NMRs), and bats possess two mechanistically similar systems to prevent the generation of mitochondrial reactive oxygen species (mROS): hexokinases I and II and creatine kinase bound to mitochondrial membranes. Both systems operate in a manner such that one of the kinase substrates (mitochondrial ATP) is electrophoretically transported by the ATP/ADP antiporter to the catalytic site of bound hexokinase or bound creatine kinase without ATP dilution in the cytosol. One of the kinase reaction products, ADP, is transported back to the mitochondrial matrix via the antiporter, again through an electrophoretic process without cytosol dilution. The system in question continuously supports H-ATP synthase with ADP until glucose or creatine is available. Under these conditions, the membrane potential, ∆ψ, is maintained at a lower than maximal level (i.e., mild depolarization of mitochondria). This ∆ψ decrease is sufficient to completely inhibit mROS generation. In 2.5-y-old mice, mild depolarization disappears in the skeletal muscles, diaphragm, heart, spleen, and brain and partially in the lung and kidney. This age-dependent decrease in the levels of bound kinases is not observed in NMRs and bats for many years. As a result, ROS-mediated protein damage, which is substantial during the aging of short-lived mice, is stabilized at low levels during the aging of long-lived NMRs and bats. It is suggested that this mitochondrial mild depolarization is a crucial component of the mitochondrial anti-aging system.
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http://dx.doi.org/10.1073/pnas.1916414117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104298PMC
March 2020

Mitochondrial Damage and Mitochondria-Targeted Antioxidant Protection in LPS-Induced Acute Kidney Injury.

Antioxidants (Basel) 2019 Jun 14;8(6). Epub 2019 Jun 14.

A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia.

Induced and frequently unwanted alterations in the mitochondrial structure and functions are a key component of the pathological cascade in many kidney pathologies, including those associated with acute damage. One of the principal pathogenic elements causing mitochondrial dysfunction in Acute Kidney Injury (AKI) is oxidative stress. After ischemia and nephrotoxic action of drugs, sepsis and systemic inflammation are the most frequent causes of AKI. As the kidney suffers from oxidative stress during sepsis, one of the most promising approaches to alleviate such damaging consequences is the use of antioxidants. Considering administration of lipopolysaccharide (LPS) as a model of sepsis, we demonstrate that the mitochondria of neonatal renal tissue are severely affected by LPS-induced AKI, with pathological ultrastructural changes observed in both the mitochondria of the renal tubular epithelium and the vascular endothelium. Upon mitochondrial damage, we evaluated the effect of the mitochondria-targeted antioxidant plastoquinol decylrhodamine 19 (SkQR1) on the development of acute renal failure in newborn rats associated with systemic inflammation induced by the administration of LPS. We found that SkQR1 administration 3 h before LPS led to decreased urinal expression of the AKI marker neutrophil gelatinase-associated lipocalin 2 (NGAL), in addition to a decrease in urea and creatinine levels in the blood. Additionally, an observed impairment of proliferative activity in the neonatal kidney caused by LPS treatment was also prevented by the treatment of rat pups with SkQR1. Thus, one of the key events for renal tissue damage in neonatal sepsis is an alteration in the structure and function of the mitochondria and the mitochondria-targeted antioxidant SkQR1 is an effective nephroprotective agent, which protects the neonatal kidney from sepsis-induced AKI.
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http://dx.doi.org/10.3390/antiox8060176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617298PMC
June 2019

The single intravenous administration of mitochondria-targeted antioxidant SkQR1 after traumatic brain injury attenuates neurological deficit in rats.

Brain Res Bull 2019 05 29;148:100-108. Epub 2019 Mar 29.

Research Center of Neurology, Volokolamskoe Shosse 80, 125367, Moscow, Russia; M.V. Lomonosov Moscow State University, A.N. Belozersky Institute of Physico-Chemical Biology, 119991, Moscow, Russia; M.V. Lomonosov Moscow State University, Biological Faculty, 119234, Moscow, Russia. Electronic address:

The protective effect of SkQR1, a mitochondria-targeted antioxidant, was investigated on the model of focal one-sided traumatic brain injury (TBI) of the sensorimotor cortex region from 1 to 7 days after the injury. TBI caused a reliable disruption of the functions of the limbs contralateral to injury focus. The intravenous single injection of SkQR1 (250 nmol/kg) but not C12R1 (a SkQR1 homologue devoid of the antioxidant group) 30 min after TBI reduced the impairment of the motor functions of the limbs. A statistically significant improvement in limb function in animals was shown using 3 different tests: limb-placing test, beam-walking test and grip strength test. A pronounced therapeutic effect appeared on the 1th day and lasted until the end of the experiment - the 7th day after TBI. Histopathological examination showed that in the group of animals that did not receive SkQR1 in the marginal layer of the lesion there was a marked increase in astroglial expression, infiltration with segmented neutrophils, and poor survivability of neurons compared with animals treated with SkQR1. The obtained results demonstrate that the single use of plastoquinone-containing mitochondria-targeted antioxidant SkQR1 at the early stages of development of traumatic brain damage can reduce TBI-related disruptions of limb functions, and that mechanisms of the brain damage after trauma are dependent on the production of mitochondrial reactive oxygen species.
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http://dx.doi.org/10.1016/j.brainresbull.2019.03.011DOI Listing
May 2019

Neuroprotective Effects of Mitochondria-Targeted Plastoquinone in a Rat Model of Neonatal Hypoxic⁻Ischemic Brain Injury.

Molecules 2018 Jul 27;23(8). Epub 2018 Jul 27.

A. N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia.

Neonatal hypoxia⁻ischemia is one of the main causes of mortality and disability of newborns. To study the mechanisms of neonatal brain cell damage, we used a model of neonatal hypoxia⁻ischemia in seven-day-old rats, by annealing of the common carotid artery with subsequent hypoxia of 8% oxygen. We demonstrate that neonatal hypoxia⁻ischemia causes mitochondrial dysfunction associated with high production of reactive oxygen species, which leads to oxidative stress. Targeted delivery of antioxidants to the mitochondria can be an effective therapeutic approach to treat the deleterious effects of brain hypoxia⁻ischemia. We explored the neuroprotective properties of the mitochondria-targeted antioxidant SkQR1, which is the conjugate of a plant plastoquinone and a penetrating cation, rhodamine 19. Being introduced before or immediately after hypoxia⁻ischemia, SkQR1 affords neuroprotection as judged by the diminished brain damage and recovery of long-term neurological functions. Using vital sections of the brain, SkQR1 has been shown to reduce the development of oxidative stress. Thus, the mitochondrial-targeted antioxidant derived from plant plastoquinone can effectively protect the brain of newborns both in pre-ischemic and post-stroke conditions, making it a promising candidate for further clinical studies.
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http://dx.doi.org/10.3390/molecules23081871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222533PMC
July 2018

Induction of autophagy by depolarization of mitochondria.

Autophagy 2018 13;14(5):921-924. Epub 2018 Mar 13.

a Belozersky Institute of Physico-Chemical Biology , Lomonosov Moscow State University , Moscow , Russia.

Mitochondrial dysfunction plays a crucial role in the macroautophagy/autophagy cascade. In a recently published study Sun et al. described the induction of autophagy by the membranophilic triphenylphosphonium (TPP)-based cation 10-(6'-ubiquinonyl) decyltriphenylphosphonium (MitoQ) in HepG2 cells (Sun C, et al. "MitoQ regulates autophagy by inducing a pseudo-mitochondrial membrane potential [PMMP]", Autophagy 2017, 13:730-738.). Sun et al. suggested that MitoQ adsorbed to the inner mitochondrial membrane with its cationic moiety remaining in the intermembrane space, adding a large number of positive charges and establishing a "pseudo-mitochondrial membrane potential," which blocked the ATP synthase. Here we argue that the suggested mechanism for generation of the "pseudo-mitochondrial membrane potential" is physically implausible and contradicts earlier findings on the electrophoretic displacements of membranophilic cations within and through phospholipid membranes. We provide evidence that TPP-cations dissipated the mitochondrial membrane potential in HepG2 cells and that the induction of autophagy in carcinoma cells by TPP-cations correlated with the uncoupling of oxidative phosphorylation. The mild uncoupling of oxidative phosphorylation by various mitochondria-targeted penetrating cations may contribute to their reported therapeutic effects via inducing both autophagy and mitochondria-selective mitophagy.
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http://dx.doi.org/10.1080/15548627.2018.1436937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070013PMC
June 2019

Mitochondria-Targeted Antioxidants SkQ1 and MitoTEMPO Failed to Exert a Long-Term Beneficial Effect in Murine Polymicrobial Sepsis.

Oxid Med Cell Longev 2017 19;2017:6412682. Epub 2017 Sep 19.

Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the Trauma Research Center of AUVA, Vienna, Austria.

Mitochondrial-derived reactive oxygen species have been deemed an important contributor in sepsis pathogenesis. We investigated whether two mitochondria-targeted antioxidants (mtAOX; SkQ1 and MitoTEMPO) improved long-term outcome, lessened inflammation, and improved organ homeostasis in polymicrobial murine sepsis. 3-month-old female CD-1 mice ( = 90) underwent cecal ligation and puncture (CLP) and received SkQ1 (5 nmol/kg), MitoTEMPO (50 nmol/kg), or vehicle 5 times post-CLP. Separately, 52 SkQ1-treated CLP mice were sacrificed at 24 h and 48 h for additional endpoints. Neither MitoTEMPO nor SkQ1 exerted any protracted survival benefit. Conversely, SkQ1 exacerbated 28-day mortality by 29%. CLP induced release of 10 circulating cytokines, increased urea, ALT, and LDH, and decreased glucose but irrespectively of treatment. Similar occurred for CLP-induced lymphopenia/neutrophilia and the NO blood release. At 48 h post-CLP, dying mice had approximately 100-fold more CFUs in the spleen than survivors, but this was not SkQ1 related. At 48 h, macrophage and granulocyte counts increased in the peritoneal lavage but irrespectively of SkQ1. Similarly, hepatic mitophagy was not altered by SkQ1 at 24 h. The absence of survival benefit of mtAOX may be due to the extended treatment and/or a relatively moderate-risk-of-death CLP cohort. Long-term effect of mtAOX in abdominal sepsis appears different to sepsis/inflammation models arising from other body compartments.
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http://dx.doi.org/10.1155/2017/6412682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625755PMC
July 2018

Mitochondria-Targeted Antioxidant SkQ1 Improves Dermal Wound Healing in Genetically Diabetic Mice.

Oxid Med Cell Longev 2017 6;2017:6408278. Epub 2017 Jul 6.

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1-40, Moscow 119992, Russia.

Oxidative stress is widely recognized as an important factor in the delayed wound healing in diabetes. However, the role of mitochondrial reactive oxygen species in this process is unknown. It was assumed that mitochondrial reactive oxygen species are involved in many wound-healing processes in both diabetic humans and animals. We have applied the mitochondria-targeted antioxidant 10-(6'-plastoquinonyl)decyltriphenylphosphonium (SkQ1) to explore the role of mitochondrial reactive oxygen species in the wound healing of genetically diabetic mice. Healing of full-thickness excisional dermal wounds in diabetic C57BL/KsJ-db/db mice was significantly enhanced after long-term (12 weeks) administration of SkQ1. SkQ1 accelerated wound closure and stimulated epithelization, granulation tissue formation, and vascularization. On the 7th day after wounding, SkQ1 treatment increased the number of -smooth muscle actin-positive cells (myofibroblasts), reduced the number of neutrophils, and increased macrophage infiltration. SkQ1 lowered lipid peroxidation level but did not change the level of the circulatory IL-6 and TNF. SkQ1 pretreatment also stimulated cell migration in a scratch-wound assay in vitro under hyperglycemic condition. Thus, a mitochondria-targeted antioxidant normalized both inflammatory and regenerative phases of wound healing in diabetic mice. Our results pointed to nearly all the major steps of wound healing as the target of excessive mitochondrial reactive oxygen species production in type II diabetes.
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http://dx.doi.org/10.1155/2017/6408278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518517PMC
April 2018

Mitochondria-targeted antioxidants as highly effective antibiotics.

Sci Rep 2017 05 3;7(1):1394. Epub 2017 May 3.

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.

Mitochondria-targeted antioxidants are known to alleviate mitochondrial oxidative damage that is associated with a variety of diseases. Here, we showed that SkQ1, a decyltriphenyl phosphonium cation conjugated to a quinone moiety, exhibited strong antibacterial activity towards Gram-positive Bacillus subtilis, Mycobacterium sp. and Staphylococcus aureus and Gram-negative Photobacterium phosphoreum and Rhodobacter sphaeroides in submicromolar and micromolar concentrations. SkQ1 exhibited less antibiotic activity towards Escherichia coli due to the presence of the highly effective multidrug resistance pump AcrAB-TolC. E. coli mutants lacking AcrAB-TolC showed similar SkQ1 sensitivity, as B. subtilis. Lowering of the bacterial membrane potential by SkQ1 might be involved in the mechanism of its bactericidal action. No significant cytotoxic effect on mammalian cells was observed at bacteriotoxic concentrations of SkQ1. Therefore, SkQ1 may be effective in protection of the infected mammals by killing invading bacteria.
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http://dx.doi.org/10.1038/s41598-017-00802-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431119PMC
May 2017

Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1.

Aging (Albany NY) 2017 02;9(2):315-339

The Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden.

MtDNA mutator mice exhibit marked features of premature aging. We find that these mice treated from age of ≈100 days with the mitochondria-targeted antioxidant SkQ1 showed a delayed appearance of traits of aging such as kyphosis, alopecia, lowering of body temperature, body weight loss, as well as ameliorated heart, kidney and liver pathologies. These effects of SkQ1 are suggested to be related to an alleviation of the effects of an enhanced reactive oxygen species (ROS) level in mtDNA mutator mice: the increased mitochondrial ROS released due to mitochondrial mutations probably interact with polyunsaturated fatty acids in cardiolipin, releasing malondialdehyde and 4-hydroxynonenal that form protein adducts and thus diminishes mitochondrial functions. SkQ1 counteracts this as it scavenges mitochondrial ROS. As the results, the normal mitochondrial ultrastructure is preserved in liver and heart; the phosphorylation capacity of skeletal muscle mitochondria as well as the thermogenic capacity of brown adipose tissue is also improved. The SkQ1-treated mice live significantly longer (335 versus 290 days). These data may be relevant in relation to treatment of mitochondrial diseases particularly and the process of aging in general.
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http://dx.doi.org/10.18632/aging.101174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361666PMC
February 2017

Neoteny, Prolongation of Youth: From Naked Mole Rats to "Naked Apes" (Humans).

Physiol Rev 2017 04;97(2):699-720

Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Moscow, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Moscow, Russia; Leibniz Institute for Zoo and Wildlife Research, Berlin, Germany; Lomonosov Moscow State University, Biological Faculty, Moscow, Russia; Lomonosov Moscow State University, Faculty of Mechanics and Mathematics, Moscow, Russia.

It has been suggested that highly social mammals, such as naked mole rats and humans, are long-lived due to neoteny (the prolongation of youth). In both species, aging cannot operate as a mechanism facilitating natural selection because the pressure of this selection is strongly reduced due to ) a specific social structure where only the "queen" and her "husband(s)" are involved in reproduction (naked mole rats) or ) substituting fast technological progress for slow biological evolution (humans). Lists of numerous traits of youth that do not disappear with age in naked mole rats and humans are presented and discussed. A high resistance of naked mole rats to cancer, diabetes, cardiovascular and brain diseases, and many infections explains why their mortality rate is very low and almost age-independent and why their lifespan is more than 30 years, versus 3 years in mice. In young humans, curves of mortality versus age start at extremely low values. However, in the elderly, human mortality strongly increases. High mortality rates in other primates are observed at much younger ages than in humans. The inhibition of the aging process in humans by specific drugs seems to be a promising approach to prolong our healthspan. This might be a way to retard aging, which is already partially accomplished via the natural physiological phenomenon neoteny.
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http://dx.doi.org/10.1152/physrev.00040.2015DOI Listing
April 2017

Low concentration of uncouplers of oxidative phosphorylation decreases the TNF-induced endothelial permeability and lethality in mice.

Biochim Biophys Acta Mol Basis Dis 2017 04 26;1863(4):968-977. Epub 2017 Jan 26.

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia. Electronic address:

Mitochondrial dysfunctions occur in many diseases linked to the systemic inflammatory response syndrome (SIRS). Mild uncoupling of oxidative phosphorylation is known to rescue model animals from pathologies related to mitochondrial dysfunctions and overproduction of reactive oxygen species (ROS). To study the potential of SIRS therapy by uncoupling, we tested protonophore dinitrophenol (DNP) and a free fatty acid (FFA) anion carrier, lipophilic cation dodecyltriphenylphosphonium (CTPP) in mice and in vitro models of SIRS. DNP and CTPP prevented the body temperature drop and lethality in mice injected with high doses of a SIRS inducer, tumor necrosis factor (TNF). The mitochondria-targeted antioxidant plastoquinonyl decyltriphenylphosphonium (SkQ1) which also catalyzes FFA-dependent uncoupling revealed similar protective effects and downregulated expression of the NFκB-regulated genes (VCAM1, ICAM1, MCP1, and IL-6) involved in the inflammatory response of endothelium in aortas of the TNF-treated mice. In vitro mild uncoupling rescued from TNF-induced endothelial permeability, disassembly of cell contacts and VE-cadherin cleavage by the matrix metalloprotease 9 (ММР9). The uncouplers prevented TNF-induced expression of MMP9 via inhibition of NFκB signaling. Water-soluble antioxidant Trolox also prevented TNF-induced activation and permeability of endothelium in vitro via inhibition of NFκB signaling, suggesting that the protective action of the uncouplers is linked to their antioxidant potential.
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http://dx.doi.org/10.1016/j.bbadis.2017.01.024DOI Listing
April 2017

Cellular and Molecular Mechanisms of Action of Mitochondria-Targeted Antioxidants.

Curr Aging Sci 2017 ;10(1):41-48

Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, GSP-1, Leninskiye Gory, Moscow, 119991, Russia.

Reactive oxygen species generated in mitochondria are an important factor contributing to mitochondrial and cellular dysfunction underlying many degenerative diseases, chronic pathologies and aging. The idea of delivering antioxidant molecules to mitochondria in vivo to treat these diseases and slow aging intensively developed in the last 20 years. Derivatives of quinones covalently conjugated to a lipophilic cation (e.g., MitoQ and SkQ) were the most extensively studied mitochondria-targeted antioxidants. These compounds have now been used in a wide range of in vitro and in vivo studies, as well as in clinical trials in humans. Here, we review recent progress in this field with a special attention on molecular mechanisms of rechargeable mitochondria-targeted antioxidants. A simple hypothesis that aging results from gradual accumulation of occasional damage inflicted by ROS to DNA, proteins and lipids is apparently insufficient. More and more pieces of evidence indicate that the damage in question is programmed. Moreover, the imbalance in ROS-dependent regulatory mechanisms and compromised ROS signaling are underlying many pathologies and aging. Chain reactions of cardiolipin peroxidation initiated by mitochondrial ROS seem to play a key role in these degenerative processes. Such reactions are specifically abolished by mitochondriatargeted antioxidants.
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http://dx.doi.org/10.2174/1874609809666160921113706DOI Listing
December 2017

Neuroprotective properties of mitochondria-targeted antioxidants of the SkQ-type.

Rev Neurosci 2016 12;27(8):849-855

In 2008, using a model of compression brain ischemia, we presented the first evidence that mitochondria-targeted antioxidants of the SkQ family, i.e. SkQR1 [10-(6'-plastoquinonyl)decylrhodamine], have a neuroprotective action. It was shown that intraperitoneal injections of SkQR1 (0.5-1 μmol/kg) 1 day before ischemia significantly decreased the damaged brain area. Later, we studied in more detail the anti-ischemic action of this antioxidant in a model of experimental focal ischemia provoked by unilateral intravascular occlusion of the middle cerebral artery. The neuroprotective action of SkQ family compounds (SkQR1, SkQ1, SkQTR1, SkQT1) was manifested through the decrease in trauma-induced neurological deficit in animals and prevention of amyloid-β-induced impairment of long-term potentiation in rat hippocampal slices. At present, most neurophysiologists suppose that long-term potentiation underlies cellular mechanisms of memory and learning. They consider inhibition of this process by amyloid-β1-42 as an in vitro model of memory disturbance in Alzheimer's disease. Further development of the above studies revealed that mitochondria-targeted antioxidants could retard accumulation of hyperphosphorylated τ-protein, as well as amyloid-β1-42, and its precursor APP in the brain, which are involved in developing neurodegenerative processes in Alzheimer's disease.
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http://dx.doi.org/10.1515/revneuro-2016-0036DOI Listing
December 2016

A mitochondria-targeted antioxidant can inhibit peroxidase activity of cytochrome c by detachment of the protein from liposomes.

FEBS Lett 2016 09 4;590(17):2836-43. Epub 2016 Aug 4.

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Russia.

Interaction of cytochrome c with cardiolipin converts this respiratory chain electron-transfer protein into a peroxidase, supposedly involved in mitochondria-mediated apoptosis initiation. Liposome membrane permeabilization provoked by peroxidase activity of the cytochrome c/cardiolipin complex has been previously shown to be suppressed by conventional antioxidants. Here, the mitochondria-targeted antioxidant SkQ1 (plastoquinonyl-decyl-triphenylphosphonium) was found to strongly inhibit both cytochrome c/cardiolipin peroxidase activity and the permeabilization of liposomes composed of phosphatidylcholine and cardiolipin. A number of binding assays revealed a significant inhibiting effect of SkQ1 on cytochrome c binding to liposomes, thus suggesting that SkQ1-mediated protection of liposomes from the cytochrome c/H2 O2 -induced permeabilization involved distortion of the cytochrome c-membrane binding. It is suggested that antioxidant and antiapoptotic effects of alkyltriphenylphosphonium cations can be related to the prevention of cytochrome c/cardiolipin interaction.
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http://dx.doi.org/10.1002/1873-3468.12319DOI Listing
September 2016

Impact of Antioxidants on Cardiolipin Oxidation in Liposomes: Why Mitochondrial Cardiolipin Serves as an Apoptotic Signal?

Oxid Med Cell Longev 2016 26;2016:8679469. Epub 2016 May 26.

School of Physics, University of Osnabrueck, 49069 Osnabrueck, Germany; School of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119991, Russia; A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia.

Molecules of mitochondrial cardiolipin (CL) get selectively oxidized upon oxidative stress, which triggers the intrinsic apoptotic pathway. In a chemical model most closely resembling the mitochondrial membrane-liposomes of pure bovine heart CL-we compared ubiquinol-10, ubiquinol-6, and alpha-tocopherol, the most widespread naturally occurring antioxidants, with man-made, quinol-based amphiphilic antioxidants. Lipid peroxidation was induced by addition of an azo initiator in the absence and presence of diverse antioxidants, respectively. The kinetics of CL oxidation was monitored via formation of conjugated dienes at 234 nm. We found that natural ubiquinols and ubiquinol-based amphiphilic antioxidants were equally efficient in protecting CL liposomes from peroxidation; the chromanol-based antioxidants, including alpha-tocopherol, were 2-3 times less efficient. Amphiphilic antioxidants, but not natural ubiquinols and alpha-tocopherol, were able, additionally, to protect the CL bilayer from oxidation by acting from the water phase. We suggest that the previously reported therapeutic efficiency of mitochondrially targeted amphiphilic antioxidants is owing to their ability to protect those CL molecules that are inaccessible to natural hydrophobic antioxidants, being trapped within respiratory supercomplexes. The high susceptibility of such occluded CL molecules to oxidation may have prompted their recruitment as apoptotic signaling molecules by nature.
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http://dx.doi.org/10.1155/2016/8679469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899610PMC
March 2017

Ubiquinol and plastoquinol triphenylphosphonium conjugates can carry electrons through phospholipid membranes.

Bioelectrochemistry 2016 Oct 28;111:23-30. Epub 2016 Apr 28.

Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia. Electronic address:

Many mitochondria-targeted antioxidants (MTAs) that comprise a quinol moiety covalently attached through an aliphatic carbon chain to the lipophilic triphenylphosphonium cation are widely used for evaluating the role of mitochondria in pathological processes involving oxidative stress. The potency of MTAs to carry electrons across biological membranes and thereby mediate transmembrane redox processes was unknown. To assess this, we measured the rate of ferricyanide reduction inside liposomes by external ascorbate. Here, we show that MTAs containing ubiquinone (MitoQ series) or plastoquinone (SkQ series) can carry electrons through lipid membranes, with the rate being inversely proportional to the length of the hydrocarbon linker group. Furthermore, this process was stimulated by the hydrophobic anion tetraphenylborate suggesting that permeation of the cationic MTA through the membrane was the rate-limiting step of the process. This conclusion was supported by the observation that the rate of MTA-induced electron transfer was insensitive to nigericin, in contrast to electron transfer mediated by neutral quinone derivatives. These findings indicate that MTAs can be utilized to transfer electrons across lipid membranes and this may be applicable to the study of the electron-transport chain in mitochondria and other natural membranes exhibiting redox processes.
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http://dx.doi.org/10.1016/j.bioelechem.2016.04.009DOI Listing
October 2016

Real-time kinetics of electrogenic Na(+) transport by rhodopsin from the marine flavobacterium Dokdonia sp. PRO95.

Sci Rep 2016 Feb 11;6:21397. Epub 2016 Feb 11.

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119234, Russia.

Discovery of the light-driven sodium-motive pump Na(+)-rhodopsin (NaR) has initiated studies of the molecular mechanism of this novel membrane-linked energy transducer. In this paper, we investigated the photocycle of NaR from the marine flavobacterium Dokdonia sp. PRO95 and identified electrogenic and Na(+)-dependent steps of this cycle. We found that the NaR photocycle is composed of at least four steps: NaR519 + hv → K585 → (L450↔M495) → O585 → NaR519. The third step is the only step that depends on the Na(+) concentration inside right-side-out NaR-containing proteoliposomes, indicating that this step is coupled with Na(+) binding to NaR. For steps 2, 3, and 4, the values of the rate constants are 4×10(4) s(-1), 4.7 × 10(3) M(-1) s(-1), and 150 s(-1), respectively. These steps contributed 15, 15, and 70% of the total membrane electric potential (Δψ ~ 200 mV) generated by a single turnover of NaR incorporated into liposomes and attached to phospholipid-impregnated collodion film. On the basis of these observations, a mechanism of light-driven Na(+) pumping by NaR is suggested.
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http://dx.doi.org/10.1038/srep21397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749991PMC
February 2016

Results of a Multicenter, Randomized, Double-Masked, Placebo-Controlled Clinical Study of the Efficacy and Safety of Visomitin Eye Drops in Patients with Dry Eye Syndrome.

Adv Ther 2015 Dec 11;32(12):1263-79. Epub 2015 Dec 11.

Institute of Mitoengineering, Lomonosov Moscow State University, Moscow, Russian Federation.

Introduction: This article presents the results of an international, multicenter, randomized, double-masked, placebo-controlled clinical study of Visomitin (Mitotech LLC, Moscow, Russian Federation) eye drops in patients with dry eye syndrome (DES). Visomitin is the first registered (in Russia) drug with a mitochondria-targeted antioxidant (SkQ1) as the active ingredient.

Methods: In this multicenter (10 sites) study of 240 subjects with DES, study drug (Visomitin or placebo) was self-administered three times daily (TID) for 6 weeks, followed by a 6-week follow-up period. Seven in-office study visits occurred every 2 weeks during both the treatment and follow-up periods. Efficacy measures included Schirmer's test, tear break-up time, fluorescein staining, meniscus height, and visual acuity. Safety measures included adverse events, slit lamp biomicroscopy, tonometry, blood pressure, and heart rate. Tolerability was also evaluated.

Results: This clinical study showed the effectiveness of Visomitin eye drops in the treatment of signs and symptoms of DES compared with placebo. The study showed that a 6-week course of TID topical instillation of Visomitin significantly improved the functional state of the cornea; Visomitin increased tear film stability and reduced corneal damage. Significant reduction of dry eye symptoms (such as dryness, burning, grittiness, and blurred vision) was also observed.

Conclusion: Based on the results of this study, Visomitin is effective and safe for use in eye patients with DES for protection from corneal damage.

Funding: Mitotech LLC.
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http://dx.doi.org/10.1007/s12325-015-0273-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679790PMC
December 2015

Neuroprotective Effects of Mitochondria-Targeted Plastoquinone and Thymoquinone in a Rat Model of Brain Ischemia/Reperfusion Injury.

Molecules 2015 Aug 11;20(8):14487-503. Epub 2015 Aug 11.

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 40, 119992 Moscow, Russia.

We explored the neuroprotective properties of natural plant-derived antioxidants plastoquinone and thymoquinone (2-demethylplastoquinone derivative) modified to be specifically accumulated in mitochondria. The modification was performed through chemical conjugation of the quinones with penetrating cations: Rhodamine 19 or tetraphenylphosphonium. Neuroprotective properties were evaluated in a model of middle cerebral artery occlusion. We demonstrate that the mitochondria-targeted compounds, introduced immediately after reperfusion, possess various neuroprotective potencies as judged by the lower brain damage and higher neurological status. Plastoquinone derivatives conjugated with rhodamine were the most efficient, and the least efficiency was shown by antioxidants conjugated with tetraphenylphosphonium. Antioxidants were administered intraperitoneally or intranasally with the latter demonstrating a high level of penetration into the brain tissue. The therapeutic effects of both ways of administration were similar. Long-term administration of antioxidants in low doses reduced the neurological deficit, but had no effect on the volume of brain damage. At present, cationic decylrhodamine derivatives of plastoquinone appear to be the most promising anti-ischemic mitochondria-targeted drugs of the quinone family. We suggest these antioxidants could be potentially used for a stroke treatment.
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http://dx.doi.org/10.3390/molecules200814487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332348PMC
August 2015

Mitochondria-targeted antioxidant SkQ1 improves impaired dermal wound healing in old mice.

Aging (Albany NY) 2015 Jul;7(7):475-85

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.

The process of skin wound healing is delayed or impaired in aging animals. To investigate the possible role of mitochondrial reactive oxygen species (mtROS) in cutaneous wound healing of aged mice, we have applied the mitochondria-targeted antioxidant SkQ1. The SkQ1 treatment resulted in accelerated resolution of the inflammatory phase, formation of granulation tissue, vascularization and epithelization of the wounds. The wounds of SkQ1-treated mice contained increased amount of myofibroblasts which produce extracellular matrix proteins and growth factors mediating granulation tissue formation. This effect resembled SkQ1-induced differentiation of fibroblasts to myofibroblast, observed earlierin vitro. The Transforming Growth Factor beta (TGFb) produced by SkQ1-treated fibroblasts was found to stimulated motility of endothelial cells in vitro, an effect which may underlie pro-angiogenic action of SkQ1 in the wounds. In vitro experiments showed that SkQ1 prevented decomposition of VE-cadherin containing contacts and following increase in permeability of endothelial cells monolayer, induced by pro-inflammatory cytokine TNF. Prevention of excessive reaction of endothelium to the pro-inflammatory cytokine(s) might account for anti-inflammatory effect of SkQ1. Our findings point to an important role of mtROS in pathogenesis of age-related chronic wounds.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543037PMC
http://dx.doi.org/10.18632/aging.100772DOI Listing
July 2015

Cytochrome cbb3 of Thioalkalivibrio is a Na+-pumping cytochrome oxidase.

Proc Natl Acad Sci U S A 2015 Jun 8;112(25):7695-700. Epub 2015 Jun 8.

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia;

Cytochrome c oxidases (Coxs) are the basic energy transducers in the respiratory chain of the majority of aerobic organisms. Coxs studied to date are redox-driven proton-pumping enzymes belonging to one of three subfamilies: A-, B-, and C-type oxidases. The C-type oxidases (cbb3 cytochromes), which are widespread among pathogenic bacteria, are the least understood. In particular, the proton-pumping machinery of these Coxs has not yet been elucidated despite the availability of X-ray structure information. Here, we report the discovery of the first (to our knowledge) sodium-pumping Cox (Scox), a cbb3 cytochrome from the extremely alkaliphilic bacterium Thioalkalivibrio versutus. This finding offers clues to the previously unknown structure of the ion-pumping channel in the C-type Coxs and provides insight into the functional properties of this enzyme.
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http://dx.doi.org/10.1073/pnas.1417071112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485098PMC
June 2015

Aging as an evolvability-increasing program which can be switched off by organism to mobilize additional resources for survival.

Curr Aging Sci 2015 ;8(1):95-109

Lomonosov Moscow State University, A. N. Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, 119992 Moscow, Russia.

During the last decade, several pieces of convincing evidence were published indicating that aging of living organisms is programmed, being a particular case of programmed death of organism (phenoptosis). Among them, the following observations can be mentioned. (1) Species were described that show negligible aging. In mammals, the naked mole rat is the most impressive example. This is a rodent of mouse size living at least 10-fold longer than a mouse and having fecundity higher than a mouse and no agerelated diseases. (2) In some species with high aging rate, genes responsible for active organization of aging by poisoning of the organism with endogenous metabolites have been identified. (3) In women, standard deviations divided by the mean are the same for age of menarche (an event controlled by the ontogenetic program) and for age of menopause (an aging-related event). (4) Inhibitors of programmed cell death (apoptosis and necrosis) retard and in certain cases even reverse the development of age-dependent pathologies. (5) In aging species, the rate of aging is regulated by the individual which responds by changes in this rate to changes in the environmental conditions. In this review, we consider point (5) in detail. Data are summarized suggesting that inhibition of aging rate by moderate food restriction can be explained assuming that such restriction is perceived by the organism as a signal of future starvation. In response to this dramatic signal, the organism switches off such an optional program as aging, mobilizing in such a way additional reserves for survival. A similar explanation is postulated for geroprotective effects of heavy muscle work, a lowering or a rise in the external temperature, small amounts of metabolic poisons (hormesis), low doses of radiation, and other deleterious events. On the contrary, sometimes certain positive signals can prolong life by inhibiting the aging program in individuals who are useful for the community (e.g., geroprotective psychological factors). Similarly, dangerous individuals can be eliminated by programmed death due to operation of progeric psychological factors. The interplay of all these signals results in the final decision of the organism concerning its aging - to accelerate or to decelerate this process. Thus, paradoxically, such an originally counterproductive program as aging appears to be useful for the individual since this program can be switched off by the individual for a certain period of time, an action that thereby increases its resources in crucial periods of life.
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July 2016

Aging As An Evolvability-Increasing Program Which Can Be Switched Off By Organism To Mobilize Additional Resources For Survival.

Curr Aging Sci 2015 Apr 22. Epub 2015 Apr 22.

Lomonosov Moscow State University, A. N. Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, 119992 Moscow, Russia.

During the last decade, several pieces of convincing evidence were published indicating that aging of living organisms is programmed, being a particular case of programmed death of organism (phenoptosis). Among them, the following observations can be mentioned [1]. Species were described that show negligible aging. In mammals, the naked mole rat is the most impressive example. This is a rodent of mouse size living at least 10-fold longer than a mouse and having fecundity higher than a mouse and no age-related diseases [2]. In some species with high aging rate, genes responsible for active organization of aging by poisoning of the organism with endogenous metabolites have been identified [3]. In women, standard deviations divided by the mean are the same for age of menarche (an event controlled by the ontogenetic program) and for age of menopause (an aging-related event) [4]. Inhibitors of programmed cell death (apoptosis and necrosis) retard and in certain cases even reverse the development of age-dependent pathologies [5]. In aging species, the rate of aging is regulated by the individual which responds by changes in this rate to changes in the environmental conditions. In this review, we consider point [5] in detail. Data are summarized suggesting that inhibition of aging rate by moderate food restriction can be explained assuming that such restriction is perceived by the organism as a signal of future starvation. In response to this dramatic signal, the organism switches off such an optional program as aging, mobilizing in such a way additional reserves for survival. A similar explanation is postulated for geroprotective effects of heavy muscle work, a lowering or a rise in the external temperature, small amounts of metabolic poisons (hormesis), low doses of radiation, and other deleterious events. On the contrary, sometimes certain positive signals can prolong life by inhibiting the aging program in individuals who are useful for the community (e.g., geroprotective psychological factors). Similarly, dangerous individuals can be eliminated by programmed death due to operation of progeric psychological factors. The interplay of all these signals results in the final decision of the organism concerning its aging - to accelerate or to decelerate this process. Thus, paradoxically, such an originally counterproductive program as aging appears to be useful for the individual since this program can be switched off by the individual for a certain period of time, an action that thereby increases its resources in crucial periods of life.
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April 2015

Methodology for use of mitochondria-targeted cations in the field of oxidative stress-related research.

Methods Mol Biol 2015 ;1265:149-59

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Bldg. 40, Leninskie Gory 1, Moscow, 119992, Russia.

For many pathological conditions, reactive oxygen species (ROS) generated in mitochondria are considered to have a role as a trigger. When mitochondrial ROS (mROS) are formed in the inner mitochondrial membrane, they initiate free radical-mediated chain reactions of lipid peroxidation and are thus especially damaging. The consequences of membrane damage are decreased electrical resistance of the membrane, oxidative damage to cardiolipin (a mitochondria specific lipid essential for functioning of respiratory chain proteins and H(+)-ATP synthase), and damage to mitochondrial DNA localized in close vicinity to the inner membrane, with consequent mitochondrial dysfunction and induction of apoptotic cascade and cell death. To target the starting point of such undesirable events, antioxidants conjugated with mitochondria-targeted, membrane-penetrating cations can be used to scavenge ROS inside mitochondria. The most demonstrative indications favoring this conclusion originate from recent discoveries of the in vivo effects of such cations belonging to the MitoQ and SkQ groups. Here we describe some essential methodological aspects of the application of mitochondria-targeted cations promising in treating oxidative stress-related pathologies.
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http://dx.doi.org/10.1007/978-1-4939-2288-8_12DOI Listing
October 2015

Mitochondria-targeted antioxidant SkQT1 decreases trauma-induced neurological deficit in rat and prevents amyloid-β-induced impairment of long-term potentiation in rat hippocampal slices.

J Drug Target 2015 May 14;23(4):347-52. Epub 2015 Jan 14.

Research Center of Neurology, Russian Academy of Medical Sciences , Moscow , Russia .

This study assesses a protective effect of a mitochondria-targeted antioxidant SkQT1 (a mixture of 10-(6'-toluquinonyl) decyltriphenylphosphonium and 10-(5'-toluquinonyl) decyltriphenylphosphonium in proportion of 1.4:1), using an open focal trauma model of the rat brain sensorimotor cortex and a model of amyloid-beta1-42 (Abeta)-induced impairment of hippocampal long-term potentiation (LTP), a kind of synaptic plasticity associated with learning and memory. It was found that a trauma-induced neurological deficit could be partially improved with daily intraperitoneal injections of SkQT1 (250 nmol/kg) for 5 days after the trauma. Neither an analog of SkQT1 without thymoquinone (C12TPP) nor original thymoquinone without a cation residue was effective to improve such conditions. In the SkQ molecule, the phosphonium cation can be replaced by the rhodamine 19 cation, with the SkQTR1 being still active in the treatment of the neurological deficit. Application of 200 nM Abeta to rat hippocampal slices impaired the induction of LTP in the hippocampal CA1 pyramidal layer. A single intraperitoneal injection of SkQT1 (250 nmol/kg body weight) made 24 h before the slice preparation prevented the harmful effect of Abeta on the LTP. Thus mitochondria-targeted antioxidants, containing thymoquinone, have neuroprotective properties.
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http://dx.doi.org/10.3109/1061186X.2014.997736DOI Listing
May 2015
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