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pSimonkey
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20/09/2019 2:22 pm  

Mitochondrial antioxidant therapies for the ataxias - Dr Mike Murphy
MRC-Dunn Human Nutrition Unit, Wellcome Trust / MRC Building, Cambridge

Scientific summary
Mitochondrial production of reactive oxygen species (ROS) and oxidative damage is thought contribute to ageing, but there are many uncertainties. Consequently there is a need to develop specific tools to manipulate mitochondrial ROS production and oxidative damage. Here I report on the development of novel antioxidants that selectively block some aspects of mitochondrial oxidative damage, possibly enabling the roles of mitochondrial oxidative stress to be inferred. One of these antioxidants, named MitoQ, is a ubiquinone derivative targeted to mitochondria by covalent attachment to a lipophilic triphenylphosphonium cation through an aliphatic carbon chain. Due to the large mitochondrial membrane potential, the cation was accumulated within mitochondria inside cells, where the ubiquinone moiety inserted into the lipid bilayer and was reduced by the respiratory chain. The ubiquinol derivative thus formed was an effective antioxidant that prevented lipid peroxidation and protected mitochondria from oxidative damage. In addition to MitoQ, many other targeted antioxidants have been developed. Selectively manipulating mitochondrial antioxidant status with targeted antioxidants may be a feasible approach to investigate the role of mitochondrial oxidative damage in ataxias.

Lay summary by Ataxia UK’s Research Projects Manager
Dr Murphy has many years’ experience in studying mitochondria, the energy-producing compartments of cells. Although he does not work directly in the ataxia field, much of his work is of relevance to some of the ataxias where mitochondrial function is disrupted, the main example being Friedreich’s ataxia.

In Friedreich’s ataxia there is a reduction in the mitochondrial protein frataxin. This leads to an increase in iron within mitochondria, and an increase in ‘reactive oxygen species’ (sometimes referred to as free radicals), that cause damage to the cells and eventually cell death. Reactive oxygen species are produced normally as by-products of the energy producing process. In order to prevent damage being done, naturally-occurring antioxidants mop up the reactive oxygen species. In Friedreich’s ataxia, with an excess of these reactive oxygen species, there are not enough safeguards in the mitochondria to prevent damage.

Dr Murphy’s interests are firstly in trying to understand what specifically causes the damage in the mitochondria, how does that lead to diseases and how can the damage be prevented in order to treat conditions such as Friedreich’s ataxia. Secondly, why are reactive oxygen species produced at all in normal cells? Do these reactive oxygen species actually have an important role? The latter question is quite speculative at this stage, but could be of importance therapeutically; if a therapy is used that removes these free radicals, could it lead to other problems?

Dr Murphy’s team has been exploring the use of antioxidants as therapeutic strategies for conditions such as Friedreich’s ataxia. One of the antioxidants they have been working on is Coenzyme Q10, which is a naturally occurring antioxidant. However, because it is insoluble in water it is not very easy for it to penetrate the mitochondria. They therefore modified this molecule to have an extension, which they called a ‘Mito tag’, and the new molecule with a derivative of CoQ10 and the ‘Mito tag’ was called MitoQ. They then showed that MitoQ enters the mitochondria, accumulates there and reduces some of the damage by some reactive oxygen species. Another benefit of MitoQ is that after its intervention it is recycled within mitochondria and can be constantly re-used.

When doing experiments in cells taken from people with Friedreich’s ataxia, they showed that MitoQ was able to reduce damage in the cells. They also compared MitoQ with idebenone (a synthetic antioxidant that is very similar to CoQ10). They found that a lower concentration of MitoQ was needed to protect from damage compared to idebenone. They thought this was because MitoQ entered the mitochondria to a greater extent than idebenone.

Their next experiments were to see if animals can tolerate and accumulate MitoQ in the mitochondria of relevant organs such as the heart and brain, and whether this gives effective protection. They have now done studies in mice and showed that it is accumulated in both the heart and the brain. They do not as yet have any results on whether they can protect against damage in animal models of Friedreich’s ataxia, but they have shown protection against heart attack in a different mouse model. The next stage is trials in people with Friedreich’s ataxia. Safety studies have now been completed in humans, and they are hoping to start Phase Two Trials to show efficacy of the drug in Friedreich’s ataxia early next year. Trials are planned in New Zealand and the US.

His team are also working on the development of other antioxidants with mitochondrial tags. The idea is to target more of the reactive oxygen species that are causing damage. This may lead to the development of a number of different antioxidants that could be tested therapeutically in combination, as they may complement each other and result in more protection. This is some of the work they are currently doing.

Dr Murphy concluded by saying that he felt that treatment with targeted antioxidants may prove to be an effective therapeutic approach for conditions such as Friedreich’s ataxia. Although not a cure, he felt they could potentially slow or prevent the progression of the condition. In addition, there may be a rationale for testing the effects of more than one antioxidant in combination in order to target the different reactive oxygen species causing damage in the mitochondria.


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pSimonkey
(@psimonkey)
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Posts: 95
20/09/2019 2:52 pm  

www.jbc.org/cgi/content/abstract/279/36/37575

Supplementation of Endothelial Cells with Mitochondria-targeted Antioxidants Inhibit Peroxide-induced Mitochondrial Iron Uptake, Oxidative Damage, and Apoptosis*
Anuradha Dhanasekaran, Srigiridhar Kotamraju, Shasi V. Kalivendi, Toshiyuki Matsunaga, Tiesong Shang, Agnes Keszler, Joy Joseph, and B. Kalyanaraman{ddagger}

From the Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

The mitochondria-targeted drugs mitoquinone (Mito-Q) and mitovitamin E (MitoVit-E) are a new class of antioxidants containing the triphenylphosphonium cation moiety that facilitates drug accumulation in mitochondria. In this study, Mito-Q (ubiquinone attached to a triphenylphosphonium cation) and MitoVit-E (vitamin E attached to a triphenylphosphonium cation) were used. The aim of this study was to test the hypothesis that mitochondria-targeted antioxidants inhibit peroxide-induced oxidative stress and apoptosis in bovine aortic endothelial cells (BAEC) through enhanced scavenging of mitochondrial reactive oxygen species, thereby blocking reactive oxygen species-induced transferrin receptor (TfR)-mediated iron uptake into mitochondria. Glucose/glucose oxidase-induced oxidative stress in BAECs was monitored by oxidation of dichlorodihydrofluorescein that was catalyzed by both intracellular H2O2 and transferrin iron transported into cells. Pretreatment of BAECs with Mito-Q (1 µM) and MitoVit-E (1 µM) but not untargeted antioxidants (e.g. vitamin E) significantly abrogated H2O2- and lipid peroxide-induced 2',7'-dichlorofluorescein fluorescence and protein oxidation. Mitochondria-targeted antioxidants inhibit cytochrome c release, caspase-3 activation, and DNA fragmentation. Mito-Q and MitoVit-E inhibited H2O2- and lipid peroxide-induced inactivation of complex I and aconitase, TfR overexpression, and mitochondrial uptake of 55Fe, while restoring the mitochondrial membrane potential and proteasomal activity. We conclude that Mito-Q or MitoVit-E supplementation of endothelial cells mitigates peroxide-mediated oxidant stress and maintains proteasomal function, resulting in the overall inhibition of TfR-dependent iron uptake and apoptosis.


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