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Targeting the Pyruvate Dehydrogenase Complex to Improve Barth Syndrome Cardiac Function

The X-linked genetic alterations in the tafazzin gene (TAZ) underlying Barth syndrome (BTHS) and their effects on modifying cardiolipin structure and function are well established. A significant gap in understanding BTHS is how cardiolipin specifically contributes to BTHS pathology—a requisite prelude for identifying a rational therapeutic approach.

The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly oxidizes pyruvate to acetyl CoA. Consequently, PDC functions as a critical energy homeostat that links cytoplasmic glycolysis to the mitochondrial tricarboxylic acid (TCA) cycle and, hence, oxidative phosphorylation (OXPHOS). Rapid regulation of PDC is mediated by reversible phosphorylation of its E1alpha subunit. In humans, 4  pyruvate dehydrogenase kinase isoforms (PDK 1-4) phosphorylate and inactivate PDC, while 2 pyruvate dehydrogenase phosphatase isoforms (PDP 1 and 2) reconstitute the active complex. We recently discovered that cardiolipin deficiency in TAZ-KO C2C12 cell mitochondria results in diminished PDC activity and increased phosphorylation of the enzyme, thereby forcing TAZ-KO cells to rely on anaplerosis to sustain TCA cycle activity. PDC activity was restored by supplementing cells with exogenous cardiolipin or by treating them with the prototypic PDK inhibitor, dichloroacetate (DCA). Additional studies showed that DCA decreased glycolysis and increased OXPHOS in these cells, thereby improving mitochondrial function.

DCA has been used for over 30 years as an investigational drug in treating numerous congenital and acquired metabolic disorders in children and adults. It is currently undergoing a federally-funded, multicenter Phase 3 trial in children with congenital PDC deficiency. Experimental research and early phase trials have reported DCA’s efficacy in the treatment of myocardial ischemia or failure, hemorrhagic or septic shock and pulmonary arterial hypertension. All these conditions exhibit hyperphosphorylation of PDC that is reversed by DCA, leading to improved cardiac function. These findings lead us to hypothesize that early post-partum DCA treatment of mice with a TAZ germline mutation can increase survival by facilitating global mitochondrial energy metabolism and improved cardiac function. We will test this postulate by determining DCA’s effects on the entire PDC/PDK/PDP axis in the myocardium. In so doing, we will also investigate whether DCA treatment in TAZ-KO survivors promotes metabolic and redox homeostasis, using targeted metabolomics and proteomics. If these preclinical studies demonstrate a beneficial effect of DCA in the TAZ-KO murine model, an early phase, mechanistically-oriented clinical trial of DCA in BTHS patients would be a logical next step.

Peter W. Stacpoole1, Charles E. McCall2, Boone M. Prentice3, , Chelsey Mertens3, Linh Vo4, Hasini Kalpage5, Maik Hüttemann5, and Miriam L. Greenberg4

  1. Departments of Medicine and Biochemistry and Molecular Biology, University of Florida, Gainesville, FL
  2. Department of Internal Medicine/Molecular Medicine, Wake Forest University, Winston-Salem, NC
  3. Department of Chemistry, University of Florida, Gainesville, FL
  4. Department of Biological Sciences, Wayne State University, Detroit, MI
  5. Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI,

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