At the turn of 1960-1970s, in 1969 V.Skulachev and his Moscow State University (MSU) colleagues, in collaboration with Prof. Yefim Liberman’s team (USSR Academy of science) were verifying the chemiosmotic hypothesis proposed by Dr. Peter Mitchell (Nobel Prize Winner in Chemistry, 1978) who postulated the existence of electric potential difference across the mitochondrial membrane. The results of their work (published in Nature, 1969, 222, 1076-8) suggested that some compounds - lipophilic cations (phosphonium ions for instance) – can be targeted to mitochondria due to the electric field on the mitochondrial membrane as the mitochondrion has a negative charge inside. Those scientists developed a general approach that led to synthesis of hydrophobic ions capable of penetrating mitochondrial membrane.
Mitochondria are well known to be organelles present in practically every eukaryotic cell. Mitochondria can be called the power stations of living cells. Inside mitochondria the electric potential formed by respiratory chain enzymes through oxidative degradation of nutrients is transformed into the energy of ATP (adenosine triphosphate) chemical bonds.
A substantial negative charge is formed inside mitochondria in the process of electric potential difference generation on the mitochondrial membrane. It is important to stress that the inner mitochondrial space is the only place in living cell which is negatively charged in relation to its external environment.
This unique mitochondrial feature was suggested to be used for targeted accumulation of positively charged substances in mitochondria. Positively charged ions (cations), were hypothesized to be accumulated in mitochondria after getting into a cell.
In order to verify this hypothesis cations of triphenylalkylphosphonium (TPP) were studied. Positively charged phosphorus atom is surrounded by hydrophobic residues in TPP. The charge is evenly distributed through the whole space around the central atom in this type of ions. Such a construction prevents ion hydration, the main reason of membrane’s impermeability for charged molecules. TPP cations proved to get accumulated in mitochondria.
Back in 1970 S.Severin, V.Skulachev and L.Yaguzhinsky suggested to use penetrating ions as “electric locomotive molecules” capable of transporting into mitochondria different substances that would be able to influence processes taking place in these organelles. Back in 1974 American biochemist David Green suggested this type of penetrating cations to be called “Skulachev ions” or “Sk”.
At the end of the 90s British scientist from Cambridge Michael Murphy connected TPP ions to antioxidants – vitamin E and ubiquinone. This work was part of the same concept of molecular electric locomotives capable of targeted transport of different substances into mitochondria. The data of Murphy et al proved MitoQ (the name given to this new substance - ubiquinone attached to TPP) to actually get accumulated in mitochondria, which resulted in protection of mitochondria and cell cultures from oxidative stress. But so far it hasn’t been possible to use these substances on a wider scale, most likely because of a strong pro-oxidant activity and lack of effectiveness in small concentrations.
Some new possibilities opened up only in the beginning of this century. In 2004, a new substance was synthesized by the group of professor Vladimir P. Skulachev in the Moscow State University. Our project team later gave the substance its “production” name “SkQ1”.
Two commercial entities Mitotech Russia and Mitotech EU were established around 2010 with an aim to develop SkQ1 into a drug targeting several age-related indications. Targeted therapeutic areas include ophthalmic and neurodegenerative disorders. The companies are running their clinical programs in different geographical markets with a common goal of making SkQ1-based drugs available to patients world-wide.