As a class of therapy to treat the mitochondrial dysfunction of age, mitochondrially targeted antioxidants are fairly advanced in their progression towards widespread use. MitoQ is classified as a supplement, and has been shown to improve cardiovascular function in older people. Plastinquinones such as SkQ1 have a fair-sized literature of animal studies and are approved for use in inflammatory eye diseases in Russia. They are going through clinical trials in Europe for a range of conditions. The mitochondrially targeted antioxidant of interest today is SS-31, which has been under clinical development for some years, and, as for SkQ1, has a fair sized literature of animal studies. In today's open access paper, researchers report on the mechanisms by which SS-31 produces improvement of mitochondrial function in an animal model of heart failure.
Mitochondria are the powerplants of the cell, conducting energetic chemical operations that result in the production of ATP, an energy store molecule used to power cellular processes. A side-effect of mitochondrial function is the generation of oxidative molecules that can produce all sorts of damage as they react with molecular machinery throughout the cell. This is consistently and constantly repaired, and even treated as a form of signaling, in the normal course of affairs. As aging progresses, greater levels of this oxidative stress occur, and mitochondria become dysfunctional in ways that can be helped by dialing back the presence of oxidative molecules in the mitochondrial themselves.
The normal sort of antioxidants sold in supplement stores have no useful effect on this problem, and in fact are counterproductive. They don't soak up oxidizing molecules in mitochondria and they do soak up the oxidizing molecules elsewhere, suppressing the benefits that arise from oxidative signaling. Hence the existence of mitochondrially targeted antioxidants.
In animal studies, mitochondrially targeted antioxidants have been shown to be beneficial in numerous age-related conditions that feature mitochondrial oxidative stress and dysfunction, which is most conditions of aging, in fact. As is the case for approaches to NAD+ upregulation targeted at improving mitochondrial function, the effect size isn't as large as one might like, but it is hard to argue with the data showing that reductions in mitochondrial oxidative stress improve cardiovascular function in humans. In animal models, a wider range of age-related conditions can be improved via delivery of this class of therapy, but it remains to be seen how many will translate well to the human case.
Mitochondria are both the primary source of organismal energy and the major source of cellular reactive oxygen species (ROS) and oxidative stress during aging. Aged cardiac mitochondria are functionally changed in redox balance and are deficient in ATP production. Numerous reported studies have focused on redox stress and ROS production in aging. However, in its simplistic form, the free radical theory of aging has become severely challenged.
While more attention has been placed on mitochondrial electron leak and consequent free radical generation, proton leak is a highly significant aspect of mitochondrial energetics, as it accounts for more than 20% of oxygen consumption in the liver and 35% to 50% of that in muscle in the resting state. There are two types of proton leak in the mitochondria: 1) constitutive, basal proton leak, and 2) inducible, regulated proton leak , including that mediated by uncoupling proteins (UCPs). In skeletal muscle, a majority of basal proton conductance has been attributed to adenine nucleotide translocase (ANT). Although, aging-related increased mitochondrial proton leak was detected in the mouse heart, kidney, and liver by indirect measurement of oxygen consumption in isolated mitochondria, direct evidence of functional impact remains to be further investigated. Moreover, the exact site and underlying mechanisms responsible for aging-related mitochondrial proton leak are unclear.
SS-31 (elamipretide) binds to cardiolipin-containing membranes and improves cristae curvature. Prevention of cytochrome c peroxidase activity and release has been proposed as its major basis of activity. SS-31 is highly effective in increasing resistance to a broad range of diseases, including heart ischemia reperfusion injury, heart failure, neurodegenerative disease, and metabolic syndrome. In aged mice, SS-31 ameliorates kidney glomerulopathy and brain oxidative stress and has shown beneficial effects on skeletal muscle performance. We have recently shown that administration of SS-31 to 24 month old mice for 8 weeks reverses the age-related decline in diastolic function, increasing the E/A ratio from just above 1.0 to 1.22, restoring this parameter 35% towards that of young (5 month old) mice. However how SS-31 benefits and protects aged cardiac cells remains unclear.
In this report we investigated the effect and underlying mechanism of action of SS-31 on aged cardiomyocytes, especially on the mitochondrial proton leak. Using the naturally aged rodent model we provided direct evidence of increased proton leak as the primary energetic change in aged mitochondria. We further show that the inner membrane protein ANT1 mediates the augmented proton entry in the old mitochondria. Most significantly, we demonstrate that SS-31 prevents the proton entry and rejuvenates mitochondrial function through direct association with ANT1 and stabilization of the ATP synthasome.