The Slow Progression of Mitochondrially Targeted Antioxidants

It was going on a decade ago that I first noticed research on antioxidant compounds that target mitochondria in cells. That was the Russian research team of Vladimir Skulachev and their family of plastinquinone compounds, with SkQ as the canonical example. They started off with a demonstration that SkQ modestly extended healthy life span in mice, which is the source of interest in mitochondrially targeted antioxidants in the longevity science community.

Why would we expect antioxidants in mitochondria to extend healthy life to some degree? Mitochondria are the power plants of the cell, generating chemical energy stores that power other cellular processes. In the course of doing this the mitochondria also create reactive oxidizing molecules that can damage molecular machinery. That damage is usually quickly repaired, but some of it can slip through the gaps to linger, multiple, and cause harmful consequences in the long-term. There is no direct relationship between the level of oxidative stress generated in a cell by its mitochondria and the pace of aging: both slight reductions (less damage) and slight increases (the cell reacts with more repair efforts, so less damage overall) have been shown to extend life in short-lived laboratory animals. Some of the most important potential damage caused by oxidizing molecules is inside mitochondria themselves, however, right at the source. This is probably why antioxidants localized mitochondria can modestly alter the progression of aging, but antioxidants everywhere else do not. There are in fact natural antioxidants produced within cells that localize to mitochondria, and researchers have demonstrated some degree of slowed aging in mice through genetic engineering that results in increased production of these mitochondrially targeted antioxidants.

The types of antioxidant you can go out and buy in a store do not localize to mitochondria and do nothing for your health. That is in fact the scientific consensus on supplements in general, derived from numerous large studies. In fact taking a lot of antioxidants is probably mildly harmful, since it interferes with the oxidative signaling that is a necessary part of the chain of mechanisms that produce benefits from exercise. Exercise causes mild cellular stress, and the raised levels of oxidative molecules generated by mitochondrial activity is a signal for cells to wake up and do something about the situation. Suppress that signal with antioxidants and exercise benefits vanish.

Over the past decade Skulachev's researchers have tested plastiquinone compounds in a variety of laboratory species. As is often the case in these matters, early life span figures settled down to a lower 10% gain or less in more careful studies, much less than can be achieved via calorie restriction, to pick one example. However, they also tested for results in the treatment of range of specific medical conditions. They eventually settled on bringing a drug to market for eye conditions shown to benefit from the actions of mitochondrial antioxidants. Unlike the life extension, these results seem much more robust and transformative. Regardless, translating research to the clinic is a slow business at the best of times, thanks to heavy-handed regulation, and at the present time the only way forward within the system is to treat a specific disease rather than the causes of aging itself. This is the case even if you happen to have an approach to hand that works somewhat better than mitochondrially targeted antioxidants.

Vladimir Skulachev isn't the only researcher with a background in mitochondrial antioxidants, and the Russian teams are not the only groups working in this area. The link I have for you today is related to a US group and their mitochondrially targeted molecule SS-31, also known as MTP-131, Bendavia, and Ocuvia. These researchers are also well down the path of commercial development via the startup Stealth Biotherapeutics. Interestingly, as this article notes, SS-31 may not even be an effective antioxidant but instead reduces oxidant levels via other means:

New Mitochondrial Therapy Based on Bioenergetics Advancing in Range of Clinical Trials

In the pipeline at Stealth Biotherapeutics is a new therapy, MTP-131, with the potential to treat individuals with mitochondrial disease and other diseases affected by mitochondrial dysfunction. The systemic version of MTP-131 (also known as Bendavia) is in clinical trials for skeletal muscle and cardio-renal diseases. The topical eye drop version (also known as Ocuvia) is on track to initiate clinical trials into Fuchs' corneal endothelial dystrophy and Leber's hereditary neuropathy in early 2016. "In collaboration with mitochondrial experts, we are looking at the organs with the most mitochondria (e.g., the heart) or that produce the most energy (e.g., muscle tissue and the eye). Mitochondrial function is involved in many different diseases. The key is which disease areas to focus."

"MTP-131 crosses the plasma membrane of cells and localizes specifically to the mitochondria." Probing further into the mechanism of action, the research team discovered that MTP-131 associates with the inner membrane of the mitochondria, where the respiratory complexes that generate ATP are located. "What's unique about that inner membrane? As it turns out, it's the only place where the phospholipid cardiolipin is found." Cardiolipin, a molecule that composes approximately 20% of the inner mitochondrial membrane's phospholipid content, differs from other phospholipid molecules such as phosphatidylcholine because it has two "phospho" head groups and four acyl chains. This unique structure gives cardiolipin a conical shape that forms a curve in the inner membrane of the mitochondria when the molecules are adjacent to each other, and helps hold the respiratory complexes in place. The binding of MTP-131 to cardiolipin may help the respiratory complexes operate more efficiently, in addition to other potential effects.

This mechanism of action sets MTP-131 apart from other investigational mitochondrial disease therapies because it directly affects bioenergetics rather than scavenges reactive oxygen species (ROS). Whereas therapeutics that neutralize ROS can potentially decrease ROS to harmfully low levels (some ROS activity is necessary in cells for signaling purposes), MTP-131 normalizes ROS levels by increasing the efficiency of mitochondria. In one experiment with old and young mice, it was shown that the mitochondria of old mice reached nearly the same level of ATP generation as that of young mice an hour after treatment with MTP-131, rising from approximately two-thirds the level of young mice. MTP-131 appears to have therapeutic effects only in abnormal or stressed mitochondria, potentially reducing the risk for side effects in patients. Additional safety studies in clinical trials are needed to determine any adverse effects of treatments.

Comments

I wonder if they are aware of the competitive threat posed by Gensight for treating Leber's hereditary neuropathy?

Posted by: Jim at January 5th, 2016 10:53 PM

I suffer from mitochondrial myopathy due to a single large-scale mtDNA deletion. Bendavia is indeed unique and I really hope it gets approved for clinical use sooner than later.

I wonder if Bendavia is in the same line as C60 (buckyballs), that is, they provide structural support for faulty mitochondria, increasing ATP output and improving the whole metabolic process. Furthermore, I guess that preserving mitochondrial integrity is key to avoid the clonal expansion of mutant mitochondria, the root cause of disease progression and its eventual clinical manifestation.

Posted by: Luis at January 10th, 2016 11:05 AM

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