Abstract P3048: Establishing The Mitochondrial Citrate Transporter As A Regulator Of Cardiac Development

Abstract

Introduction: Mitochondria are essential to provide oxidative energy to fuel excitation-contraction coupling of the postnatal heart. The role of mitochondrial energy production systems in the hypoxic environment of the embryonic heart is less clear, but defects in mitochondrial energy production machinery are associated with ventricular wall defects such as left ventricular noncompaction. In developing models to study mitochondrial function specifically in the postnatal mouse heart, we uncovered an unexpected embryonic-lethal knockout model that suggested roles for mitochondrial function in heart development. Uncovering mechanisms connecting mitochondrial function to the tightly regulated process of ventricular wall morphogenesis could reveal novel roles for mitochondria during development and guide further studies of developmental heart defects. Hypothesis: The mitochondrial citrate carrier (SLC25A1), a mitochondrial inner membrane transporter implicated in regulating mitochondrial function in neurons, is essential for ventricular wall morphogenesis and cardiac development. Methods and Results: We investigated the role of the mitochondrial citrate carrier (SLC25A1) in cardiac development. Slc25a1 knockout mice display impaired growth and do not survive past embryonic day (E) 18.5. Hearts from E18.5 Slc25a1 knockout embryos display a striking array of cardiac malformations including persistence of an expanded zone of trabeculated myocardium, reduced compact myocardium, and ventricular septal defects. Analysis of mitochondrial structure and function revealed that loss of Slc25a1 causes mitochondrial ultrastructural defects and depressed mitochondrial respiration. Conclusions: Our results highlight a novel role for SLC25A1 in cardiac development with specific roles in regulating both ventricular wall development and mitochondrial energetics during heart morphogenesis. Ongoing work will identify the mechanisms by which SLC25A1—a mitochondrial transporter that is not a primary component of the mitochondrial oxidative phosphorylation system—regulates mitochondrial energetics, which will help us delineate new pathways connecting mitochondria to heart development.