How Visomitin Works

Scientists have found out how the world's first drug that protects the mitochondria of a cell from damage by aggressive oxygen works

MSU Press Service

An international group of scientists led by researchers from Lomonosov Moscow State University managed to clarify the molecular mechanism of action of a drug created in Russia that protects the mitochondria of a cell from damage by aggressive forms of oxygen. This work was published in the journal Oxidative Medicine and Cellular Longevity (Lokhmatikov et al., Impact of antioxidants on cardiolipin oxidation in liposomes: Why mitochondrial cardiolipin serves as an apoptotic signal?).

Recently, Russian researchers led by Academician Vladimir Petrovich Skulachev managed to create an antioxidant drug that accumulates in mitochondria and protects them from damage. Under the commercial name "Visomitin", the drug is used in the treatment of eye diseases such as cataracts and dry eye. Armen Mulkijanyan, professor at the Faculty of Bioengineering and Bioinformatics of Lomonosov Moscow State University and Osnabrück University in Germany, told why very small doses of artificial antioxidants like Visomitin give a pronounced therapeutic effect, despite the presence of large amounts of natural antioxidants in mitochondria.

Mitochondria are intracellular structures that carry out respiration. During respiration, however, reactive oxygen species (ROS) can be formed as byproducts that can damage mitochondria. Since as mitochondria are damaged, they produce more and more ROS that are dangerous for the cell, there are mechanisms for destroying damaged mitochondria and cells, such as mitophagy and apoptosis. These mechanisms are triggered by the cell after a signal about malfunctions inside the mitochondria passes out through the double membrane surrounding the mitochondria. It has been shown in a number of laboratories that it is possible to avoid cell damage and decay by preventing the oxidation of one of the components of mitochondrial membranes – cardiolipin, since it is the oxidized cardiolipin molecules that serve as the first elements of this signaling chain.

The group of Academician of the Russian Academy of Sciences Vladimir Skulachev, Dean of the Faculty of Bioengineering and Bioinformatics of Moscow State University and Director of the Institute of Physico-Chemical Biology named after A.N. Belozersky Moscow State University, has developed a line of mitochondrially targeted antioxidants, the so-called SkQ-ions, specifically protecting cardiolipin molecules in mitochondria from oxidation by reactive oxygen species. In animal studies, SkQ-ions cured inflammatory eye diseases, helped to get out of conditions that simulated ischemia, and even reduced the manifestation of senile symptoms. Although drugs similar in mechanism of action have been obtained and are being studied in laboratories in the USA and the UK, it was the Russian group that managed to be the first to certify the drug as a medicine – eye drops. Scientists hope that SkQ drugs in the form of tablets and injections – after their certification – will help to remove the pathological symptoms accompanying strokes, heart attacks and severe injuries.

Armen Mulkidzhanyan and co-authors managed to offer answers to questions that previously baffled scientists. So, it was not clear why cardiolipin was specifically oxidized from all the components of the membrane. Its molecules make up about 10-20% of all membrane lipids, but they are specifically oxidized by ROS and, when oxidized, trigger cell self-destruction. Secondly, it was unclear why in the case of cardiolipin, natural antioxidants – coenzyme Q (ubiquinol) and vitamin E (alpha-tocopherol), which are present in large quantities in mitochondrial membranes, do not work. It remained a mystery why these substances did not protect cardiolipin from oxidation, while artificial, mitochondrial-directed antioxidants, developed by both the Skulachev group in Moscow and their colleagues in the USA and Great Britain, coped with this task perfectly, despite very small doses of drugs administered.

Armen Mulkidzhanyan says that the task of the research was set by Academician Skulachev: "Vladimir Petrovich asked our group in Germany to sort out these riddles," says Armen Mulkidzhanyan. – Most of the work was done by graduate students and MSU staff who worked both in Russia and in Germany, so their contribution was decisive. As for the study itself, we have developed an experimental system in which it is possible to quantify the oxidation of cardiolipin membranes and the ability of various antioxidants to prevent it. It turned out that SkQ-ions and coenzyme Q molecules protect cardiolipin membranes from oxidation equally well, but vitamin E copes with this much worse." 

Scientists were able to understand why cardiolipin molecules are the main target of ROS by comparing the experimental results with their previously obtained data and structures of respiratory enzymes. Some of the cardiolipin molecules are hidden inside respiratory protein complexes, and those that generate reactive oxygen species. "It is these molecules," says Mulkijanyan, "that should be oxidized first."

These "hidden" cardiolipin molecules, however, cannot be reached by bulky, water-insoluble coenzyme Q molecules, unlike small, nimble molecules of artificial antioxidants; they are shown in the study to be able to protect cardiolipin molecules from oxidation both from the membrane and interacting with them from the aqueous phase. 

"The point of our work," says Armen Mulkijanyan, "is that we have proposed a mechanism of action that explains how very low doses of mitochondrial–directed antioxidants provide a pronounced therapeutic effect against the background of large amounts of natural antioxidants, which are completely ineffective in this case. This mechanism is common to the entire class of similar drugs. We hope that the results of our work will help in the development of new drugs."

Portal "Eternal youth" http://vechnayamolodost.ru  13.05.2016