Therapeutic use of dichloroacetate in treatment of perinatal mitochondrial deficiency and cardiac dysfunction

University Of Florida, Gainesville FL

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Abstract

Project Summary The transition from fetal to neonatal life comes with profound changes in metabolism and in cardiac function. Changes in fetal cellular metabolism, as occur in fetal hypoxia or asphyxia, are known to impact mitochondrial function. In an animal model with elevated maternal cortisol in late gestation, mimicking mild but chronic stress, we have found a changes in gene expression in the fetal heart suggesting changes in glucose metabolism, mitochondrial function, and energy availability, with a decrease in mitochondrial number. In this model there is also an increase incidence of stillbirth, with an increase in incidence of fetal arrhythmias, including bradycardia, prolonged PR and ST intervals, and reduced fetal aortic pressure at birth. The proposed studies will use this model to test the overarching hypothesis that this phenotype can be rescued using dichloroacetate, a small molecule therapeutic that has been effectively used in congenital diseases affecting mitochondrial function, as well as in adult myocardial ischemia. DCA increases activity of the pyruvate dehydrogenase complex (PDC), which is required for TCA cycle activity, mitochondrial survival, and oxidative metabolism. DCA will be administered acutely during labor, the time at which the abnormalities in ECG become evident in our model. We will test for effectiveness of DCA to improve PDC activity and metabolic status of the heart, including mitochondrial number and function, and the metabolome related to TCA cycle function, as well as its ability to reverse measures of cardiac dysfunction, including arrhythmias and heart failure. The data from this study would potentially provide a therapeutic method for acute rescue of neonates with pathophysiologies that limit mitochondrial function.