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Correcting mitochondrial ROS production to decrease Barth syndrome symptoms

Correcting mitochondrial ROS production to decrease Barth syndrome symptoms
Renata Goncalves, PhD, Postdoctoral Research Associate, Harvard T. H. Chan School of Public Health, Boston, MA

Award—US $50,000 over 1-year period


The goal of this application is to characterize the mitochondrial sites that start to produce more Reactive Oxygen Species (ROS) in cardiac and skeletal muscle in Barth syndrome (BTHS) and to normalize specifically these aberrant sites using a novel class of mitochondrial ROS suppressors identified by our group. Mitochondrial ROS production is considered a key intermediate in the pathogenesis of BTHS, an X-linked disorder caused by mutations in tafazzin and characterized by loss of cardiolipin and severe cardiomyopathy. There are at least ten sites in the mitochondria that can produce significant amounts of ROS. Which of these sites misbehave in BTHS is unknown. The use of antioxidants indiscriminately reduces ROS levels and fails to improve disease outcome maybe because i) they do not prevent ROS formation in the first place since antioxidants just remove free radicals after they are formed and have caused damage; and ii) they also wipeout the normal levels of ROS, and skeletal and cardiac muscle rely on these species for cell signaling, differentiation, preconditioning and exercise adaptation. Our approach is to specifically prevent the excessive mitochondrial oxidant species production directly at the site(s) that misbehave when cardiolipin is not properly modified in BTHS. In intact cells it is currently impossible to discriminate which sites are responsible for the ROS production. We developed a new strategy to measure mitochondrial ROS production ex vivo and assess all the sites active in a particular physiological or pathological condition. Our preliminary data using rodent skeletal muscle mitochondria shows that at rest five sites are active and that 50% of the superoxide produced originates from complex I and surprisingly from complex II. This system will be used to characterize the specific sites with higher ROS production in BTHS. Using a high-throughput screen of 600,000 compounds, our group has found novel suppressors of mitochondrial ROS production that do not affect oxidative phosphorylation. Unlike antioxidants, these compounds suppress the radical production at its site of formation, therefore no damage is caused. These compounds will be used to correct the abnormal ROS production at the specific misbehaved site(s)in the mitochondria from tafazzin deficient mice. 

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