Translating murine Taz deficiency to human Barth syndrome: Focus on impaired lipid oxidation
Adam Chicco, PhD, Associate Professor, Colorado State University, Fort Collins, CO
Award—US $49,998 over 1-year period
*Partial funding for this award was provided by Barth Syndrome Trust
Accumulating evidence from Barth Syndrome (BTHS) patients and the taz shRNA (taz) mouse model indicate that tafazzin dysfunction preferentially impairs the utilization of fatty acids as an energy source, forcing an increased reliance on gluconeogenesis and glycolysis to meet energy demands. The cellular/molecular mechanisms underlying this effect are not well understood, as is the homology of such mechanisms between tafazzin deficiency in mice vs. tafazzin mutations in humans. Thus, it remains unclear how effectively information gained from studies in the taz mouse will be translatable to humans for development of new therapeutic approaches to BTHS. We hypothesize that tafazzin dysfunction impairs the physical coupling of fatty acid oxidation to the electron transfer system in the mitochondrial inner membrane, leading to reduced fatty acid OXPHOS control and increased production of reactive oxygen species (ROS) in tissues that rely heavily on fatty acids for energy (e.g., the heart). This primary defect results in a distinct metabolic and proteomic remodeling of the taz mouse heart that may be initially adaptive, but ultimately becomes maladaptive, contributing to cardiomyopathy and the complex BTHS phenotype seen in humans.