SkQ is a class of mitochondria-targeted

antioxidants Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricants, ...

, developed by Professor Vladimir Skulachev and his team. In a broad sense, SkQ is a

lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...

cation, linked via saturated hydrocarbon chain to an antioxidant. Due to its

properties, SkQ can effectively penetrate through various cell membranes. The positive charge provides directed transport of the whole molecule including antioxidant

moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...

into the negatively charged mitochondrial matrix. Substances of this type, various drugs that are based on them, as well as methods of their use are patented in Russia and other countries such as United States, China, Japan, and in Europe. Sometimes the term SkQ is used in a narrow sense for the denomination of a cationic derivative of the plant antioxidant

plastoquinone Plastoquinone (PQ) is an isoprenoid quinone molecule involved in the electron transport chain in the light-dependent reactions of photosynthesis. The most common form of plastoquinone, known as PQ-A or PQ-9, is a 2,3-dimethyl-1,4-benzoquinone m ...

History

In 1969, triphenylphosphonium (TPP, charged triphenylphosphine) was proposed for use for the first time. This compound with a low molecular weight consists of a positively charged

phosphorus Phosphorus is a chemical element with the symbol P and atomic number 15. Elemental phosphorus exists in two major forms, white phosphorus and red phosphorus, but because it is highly reactive, phosphorus is never found as a free element on Ear ...

atom and surrounded by three hydrophobic

phenyl In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...

s that are accumulating in mitochondria. In 1970, the use of the TPP for targeting the delivery of compounds to the mitochondrial matrix was proposed. In 1974, the TPP, as well as its derivatives and other penetrating

ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

s, were named "Skulachev’s Ions" by the famous American biochemist

David E. Green David Ezra Green (August 5, 1910 – July 8, 1983) was an American biochemist who made significant contributions to the study of enzymes, particularly the electron transport chain and oxidative phosphorylation. Life and career Green was born i ...

. In 1999, the first work on the directed delivery of the antioxidant alpha-tocopherol linked by a hydrocarbon chain to TPP to the mitochondria was published. The compound was named TPPB or MitoVitE. Several years later MitoQ, a better version of a mitochondria-targeted compound was synthesized. Its antioxidant part is represented by

ubiquinone Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10. It is a 1,4-benzoq ...

, which is linked with a 10-carbon

aliphatic chain In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane, o ...

to TPP. In the early 2000s, a group of researchers led by prof V. P. Skulachev in

Moscow State University M. V. Lomonosov Moscow State University (MSU; russian: Московский государственный университет имени М. В. Ломоносова) is a public research university in Moscow, Russia and the most prestigious ...

began the development of SkQ — the mitochondrial-targeted antioxidant, similar to MitoQ, but with the ubiquinone replaced with plastoquinone (more active analog of ubiquinone derived from plant chloroplasts). Since 2005, several modified SkQ compounds were synthesized and tested

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...

, the efficiency and the antioxidant effects of the tested compounds were higher than previous analogs by hundreds of times. All of these compounds have abbreviated names derived from the names of Skulachev (Sk), letters for quinone (Q) and denote the modification (alpha and/or numeric symbol, for example, R1 for a derivative of

rhodamine Rhodamine is a family of related dyes, a subset of the triarylmethane dyes. They are derivatives of xanthene. Important members of the rhodamine family are Rhodamine 6G, Rhodamine 123, and Rhodamine B. They are mainly used to dye paper and inks ...

and plastoquinone). The largest amount of data was obtained for SkQ1 and SkQR1. Later SkQ properties were tested in vitro on

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...

and

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

in different organisms: mice, drosophilids,

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constit ...

, and many others. It was found that SkQ is able to protect cells from death from

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

and is effective as a treatment of

age-related disease An aging-associated disease (commonly termed age-related disease, ARD) is a disease that is most often seen with increasing frequency with increasing senescence. They are essentially complications of senescence, distinguished from the aging proc ...

s in animals. Since 2008, the development of pharmaceuticals based on SkQ has been started. In 2012, The

Ministry of Health of the Russian Federation The Ministry of Health of the Russian Federation (russian: Министерство здравоохранения Российской Федерации, in short russian: Минздрав России, translit=Minzdrav Rossii) is a ministry of ...

approved the use of the

eye drops Eye drops or eyedrops are liquid drops applied directly to the surface of the eye usually in small amounts such as a single drop or a few drops. Eye drops usually contain saline to match the salinity of the eye. Drops containing only saline ...

"Visomitin" based on SkQ1 for the treatment of

dry eye syndrome Dry eye syndrome (DES), also known as keratoconjunctivitis sicca (KCS), is the condition of having dry eyes. Other associated symptoms include irritation, redness, discharge, and easily fatigued eyes. Blurred vision may also occur. Symptoms range ...

and the early stage of cataract. Testing of the efficacy of SkQ-drugs against other diseases, both in Russia and in the United States is currently in progress. In 2016, phase 1 of a clinical trial of an oral drug containing SkQ1 was conducted in Russia. In 2017, it was found that SkQ has a strong

antibacterial An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...

effect and is able to inhibit the activity of multidrug-resistant

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

s in

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...

Since 2019 the Skulachev project is developing mitochondrial antioxidants in several areas: synthesis and testing of new SkQ compounds, testing the effects on a variety of model systems and in different diseases.

Classification

SkQ compound consists of three parts: antioxidant, C-aliphatic linker and lipophilic cation. SkQ and related compounds

A list of some of SkQ and substances with similar structure:

By type of cation

Lipophilic cation determines the efficiency of penetration through the

membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. ...

s into the mitochondrial matrix. The best properties are shown by SkQ-compounds with triphenylphosphonium ion (TPP): MitoQ, SkQ1, and others. Similar penetration efficiency was shown for compounds with rhodamine 19, such as SkQR1. Rhodamine has

fluorescence Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation. It is a form of luminescence. In most cases, the emitted light has a longer wavelength, and therefore a lower photon energy, tha ...

properties, so its derivatives are used in the visualization of mitochondria. The SkQ derivatives with acetylcarnitine (SkQ2M) tributyl ammonium (SkQ4) as lipophilic cations have weak penetrating properties. The cations with the well-known medical properties —

berberine Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in such plants as ''Berberis vulgaris'' (barberry), '' Berberis aristata'' (tree turmeric), '' Mahonia aquifolium'' (Oregon grape), '' Hyd ...

and

palmatine Palmatine is a protoberberine alkaloid found in several plants including ''Phellodendron amurense'', ''Coptis Chinensis'' (Rhizoma coptidis, chinese goldthread) and '' Corydalis yanhusuo'', ''Tinospora cordifolia'' (gurjo, heart-leaved moonseed), ...

were also tested. SkQBerb and SkQPalm – SkQ derivatives, do not differ much in properties from SkQ1 and SkQR1.

The length of the linker

In SkQ compounds, a decamethylenic linker (an

of 10 carbon atoms) is used. Reduction of the length of the chain leads to a deterioration in the penetrating ability of ions. The compound with such pentamethylenic linker is demonstrated on SkQ5.

Molecular dynamics Molecular dynamics (MD) is a computer simulation method for analyzing the physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a fixed period of time, giving a view of the dynamic "evolution" of t ...

in the membrane calculated with a computer have shown that the length of the linker of 10 is optimal for the manifestation of antioxidant properties of SkQ1. The quinone residue is located right next to the C9 or C13 atoms of the

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...

s of the membrane that has to be protected from oxidative damage.

The type of antioxidant

Compounds without antioxidant part are used to control the effect of SkQ compound. For example, C₁₂-TPP and C₁₂R1 penetrate the mitochondria but do not inhibit the

oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...

. Interestingly, these compounds partially demonstrate the positive effects of SkQ. This happens due to the phenomenon of soft

depolarization In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is ess ...

(mild uncoupling) of the mitochondrial membrane. Compounds with

tocopherol Tocopherols (; TCP) are a class of organic chemical compounds (more precisely, various methylated phenols), many of which have vitamin E activity. Because the vitamin activity was first identified in 1936 from a dietary fertility factor in rat ...

and ubiquinone for historical reasons are called MitoVitE and MitoQ, although formally they can be attributed to the class of SkQ-compounds. MitoQ is traditionally used for comparison with the SkQ compound. The highest antioxidant activity was shown for the compounds with thymoquinone (SkQT1 and SkQTК1). Thymoquinone is a derivative of plastoquinone, but with one methyl substituent in the aromatic ring. Next in the sequence of antioxidant activity connection is plastoquinone (SkQ1 and SkQR1), with two methyl substituents. SkQ3 is a less active compound, with three methyl substituents. SkQB without methyl substituents exhibits the weakest antioxidant properties. In general, SkQ-like compounds can be arrange by its antioxidant activity as follows: SkQB < MitoQ < DMMQ ≈ SkQ3 < SkQ1 < SkQT.

Mechanism of action

The positive effect of SkQ is associated with its following properties: * penetration into the mitochondria — the main source of reactive oxygen species (ROS) of the cells * inhibition of ROS at the site of their formation in two different ways: * direct neutralization of ROS due to the oxidation of plastoquinone, * reduction of mitochondrial membrane potential

Penetration into the mitochondria

Due to its lipophilic properties, SkQ-substances can penetrate the

lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...

. The transportation is caused by the electrical potential due to the presence of a positive charge in SkQ. Mitochondria are the only intracellular organelles with a negative charge. Therefore, SkQ effectively penetrates and accumulates there. The accumulation coefficient can be estimated using the

Nernst equation In electrochemistry, the Nernst equation is a chemical thermodynamical relationship that permits the calculation of the reduction potential of a reaction ( half-cell or full cell reaction) from the standard electrode potential, absolute tempe ...

. To do this, we must take into account that the potential of the plasma membrane of the cell is about 60 mV (the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

has a negative charge), and the potential of the mitochondrial membrane is about 180 mV (the matrix has a negative charge). As a result, the electric gradient SkQ between the extracellular medium and the mitochondrial matrix is 10⁴. It should also be taken into account that SkQ has a high coefficient of distribution between lipid and

water Water (chemical formula ) is an Inorganic compound, inorganic, transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living ...

, about 10⁴. Taking this into account, the total concentration gradient of SkQ inside the inner layer of the inner mitochondria membrane can be up to 10⁸.

Direct inhibition of ROS

Oxidation of organic substances by ROS is a chain process. Several types of active free radicals —

peroxide In chemistry, peroxides are a group of compounds with the structure , where R = any element. The group in a peroxide is called the peroxide group or peroxo group. The nomenclature is somewhat variable. The most common peroxide is hydrogen ...

(RO₂^*), alkoxyl (RO*),

alkyl In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl is derived from a cycloa ...

(R*), and ROS ( superoxide anion, singlet oxygen), participate in these chain reactions. One of the main targets of ROS — cardiolipin, polyunsaturated phospholipid of the inner membrane of mitochondria, which is especially sensitive to peroxidation. After a radical attack on the C₁₁ atom of

linoleic acid Linoleic acid (LA) is an organic compound with the formula COOH(CH2)7CH=CHCH2CH=CH(CH2)4CH3. Both alkene groups are ''cis''. It is a fatty acid sometimes denoted 18:2 (n-6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid. ...

, cardiolipin forms peroxyl radical, which is stabilized at positions C₉ and C₁₃ due to its neighboring double bonds. The location of the SkQ1 in the mitochondrial membrane is that the plastoquinone residue is exactly near of C₉ or C₁₃ of cardiolipin (depending on the SkQ conformation). Thus, it can quickly and effectively quench the peroxyl radical of cardiolipin. Another important property of SkQ is its recyclability. After ROS neutralization the SkQ antioxidant moiety is converted to its oxidized form (plastoquinone or semi-quinone). Then it can be quickly restored by the complex III of the

respiratory chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples thi ...

. Thus, due to the functioning of the respiratory chain, SkQ exists mainly in a restored, active form.

Uncoupling properties

In some cases (for example, in experiments on the lifespan of Drosophila or plant models) compound C₁₂-TPP (without the plastoquinone residue) can successfully substitute for SkQ1. This phenomenon is explained by the fact that any hydrophobic compound with a delocalized positive charge is able to transfer anions of fatty acids from one side of the membrane to another, thus lowering the transmembrane potential. This phenomenon is called uncoupling of respiration and

ATP synthesis ATP synthase is a protein that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). It is classified under ligases as it changes ADP by the formation ...

on the mitochondrial membrane. In the cell, this function is normally performed by uncoupling proteins (or UCPs, including

thermogenin Thermogenin (called uncoupling protein by its discoverers and now known as uncoupling protein 1, or UCP1) is a mitochondrial carrier protein found in brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis, and ma ...

from brown fat adipocytes) and ATP/ADP antiporter. Weak depolarization of the membrane leads to a multiple reductions in the amount of ROS produced by mitochondria.

Pro-oxidant effect

At high concentrations (micromolar and more) SkQ-compounds exhibit pro-oxidant properties stimulating ROS production. The advantage of SkQ1 is that the difference in concentrations between pro- and antioxidant activity is about 1000 fold. Experiments on mitochondria have shown that SkQ1 begins to exhibit antioxidant properties already at concentrations of 1 nM, and pro-oxidant properties at concentrations of about 1 μM. For comparison, this "concentration window" of MitoQ is only about 2-5 fold. The manifestation of antioxidant activity of MitoQ begins only with concentrations of 0.3 μM while it begins to demonstrate pro-oxidant effect at 0.6-1.0 μM.

Anti-inflammatory effect

In several experimental models (including experiments on

laboratory animals Animals used by laboratories for testing purposes are largely supplied by dealers who specialize in selling them to universities, medical and veterinary schools, and companies that provide contract animal-testing services. It is comparatively rare ...

) SkQ1 and SkQR1 showed a pronounced anti-inflammatory effect.

Suppression of multiple drug resistance

SkQ1 and C₁₂-TPP are substrates of ABC-transporters. The main function of these enzymes is the protection of cells from

xenobiotics A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...

. Lipophilic cations compete with other substrates of these carriers and thus weaken the protection of cells from external influences.

Use

Medicine

SkQ is able to delay the development of several traits of aging and increase the life span in a variety of animals. Depending on the type of SkQ molecule, the substance may reduce early mortality, increase life expectancy and extend the maximum age of experimental animals. Also in various experiments, SkQ has slowed down the development of several age-dependent pathologies and signs of aging. It was shown that SkQ accelerates

wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...

, as well as treats age-related diseases such as osteoporosis,

cataracts A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...

retinopathy Retinopathy is any damage to the retina of the eyes, which may cause vision impairment. Retinopathy often refers to retinal vascular disease, or damage to the retina caused by abnormal blood flow. Age-related macular degeneration is technically inc ...

, and others. At the end of 2008, preparations for the official approval of SkQ-based pharmaceuticals in Russia has started. The efficiency of eye drops against "

" was also confirmed in the following double-blind

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. In general, placebos can af ...

-controlled studies: (a) international multicenter study in Russia and

Ukraine Ukraine ( uk, Україна, Ukraïna, ) is a country in Eastern Europe. It is the second-largest European country after Russia, which it borders to the east and northeast. Ukraine covers approximately . Prior to the ongoing Russian inv ...

, phase II study in the United States. A clinical study on patients with age-related cataracts was also successfully conducted. In Russia in 2019 clinical studies are in progress for two improved versions of SkQ1-based eye drops – Visomitin Forte (phase II study on patients with age-related

macular degeneration Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...

) and Visomitin Ultra (Phase I clinical study). In 2018-2021, both attempts at Phase III clinical trails in the United States failed to show any statistically significant results among 452 (VISTA-1/NCT03764735) and 610 (VSTA-2/NCT04206020) participants respectively.

Cosmetology

SkQ1 is included in the composition of cosmetic products such as Mitovitan Active, Mitovitan, and Exomitin.

Veterinary

The drug "Visomitin" on the basis of SkQ1 used in veterinary practice for the treatment of ophthalmologic diseases in pets. In particular, the effectiveness is shown for the treatment of retinopathy in

dog The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the wolf. Also called the domestic dog, it is derived from the extinct Pleistocene wolf, and the modern wolf is the dog's nearest living relative. Do ...

cat The cat (''Felis catus'') is a domestic species of small carnivorous mammal. It is the only domesticated species in the family Felidae and is commonly referred to as the domestic cat or house cat to distinguish it from the wild members of ...

s, and

horse The horse (''Equus ferus caballus'') is a domesticated, one-toed, hoofed mammal. It belongs to the taxonomic family Equidae and is one of two extant subspecies of ''Equus ferus''. The horse has evolved over the past 45 to 55 million yea ...

Else

Experiments have shown an unexpected effect of SkQ on plants. The substance stimulated differentiation (in the treatment of

callus A callus is an area of thickened and sometimes hardened skin that forms as a response to repeated friction, pressure, or other irritation. Since repeated contact is required, calluses are most often found on the feet and hands, but they may o ...

) and

seed germination Germination is the process by which an organism grows from a seed or spore. The term is applied to the sprouting of a seedling from a seed of an angiosperm or gymnosperm, the growth of a sporeling from a spore, such as the spores of fungi, fern ...

(patent US 8,557,733), increased the yield of different crops (Ph.D. thesis of A.I. Uskov).

References

{{Reflist

External links

Biomedical project "Skulachev ions" in Moscow
Membrane biology Mitochondria Dietary antioxidants Senescence