Russian researchers discovered why a natural antioxidant fails to protect a mitochondrial protein, cardiolipin, from the actions of reactive oxygen species, while a synthetic drug, Visomitin, does a good job. The discovery may pave the way for improved treatments of mitochondrial conditions linked to oxidative stress.
Their study, “Impact of antioxidants on cardiolipin oxidation in liposomes: Why mitochondrial cardiolipin serves as an apoptotic signal?”, was published in the journal Oxidative Medicine and Cellular Longevity.
Since reactive oxygen species are formed as by-products during energy-producing processes in mitochondria, these cellular structures are always at risk of oxidative damage. To protect them, damaged mitochondria and the cells holding them are disposed of through pathways triggered by a molecule called cardiolipin on the mitochondrial surface, flagging the presence of oxidative damage.
Earlier studies have shown that preventing oxidation of this particular molecule may also prevent the activation of the pathways leading to cell death. These findings led to the development of a line of drugs targeting the oxidation of cardiolipin — called SkQ-ions — by a research team at Lomonosov Moscow State University.
The antioxidant Visomitin, one of the SkQ drugs, is approved in Russia as eye drops for cataracts and dry eyes. But, up to now, it has not been clear why this synthetic compound manages a task that a naturally occurring antioxidant, known to exist in high levels within mitochondria, fails to perform.
Researchers analyzed properties of Visomitin and the naturally occurring antioxidants coenzyme Q and vitamin E, and found that the SkQ-ions and coenzyme Q protected cardiolipin from oxidation equally well, while vitamin E largely failed on this task.
They also found that cardiolipin molecules are located in such a position within the respiratory complex of the mitochondria that they are more exposed to reactive oxygen species than other proteins, explaining why, despite constituting only a minor part of the mitochondrial membrane proteins, they are highly susceptible to oxidation.
Cardiolipin’s position also explained why coenzyme Q could not prevent its oxidation. Coenzyme Q is a large, water-insoluble factor and cannot reach the cardiolipin. In contrast, the SkQ-ions are small molecules that could access cardiolipin both from the mitochondrial membrane and from the aqueous phase.
“The essence of our work is that we have proposed a mechanism that explains how very low doses of mitochondria-targeted antioxidants could provide a distinct therapeutic effect, even being applied over large amounts of natural antioxidants, which were ineffective in this case,” said Professor Armen Mulkidjanian, a co-author of the study, in a press release. “The mechanism should be valid for the whole class of similar drugs. We hope that our findings would help to develop new drugs.”