Establishing The Mitochondrial Citrate Transporter As A Regulator Of Cardiac Morphogenesis

Congenital heart disease (CHD) results from structural and functional defects of the heart that arise during embryonic development. CHD represents the most common type of birth defect and in the United States alone, affects ~1% of births per year. One common genetic cause of CHD is 22q11.2 deletion syndrome (22q11.2DS), where ~75% of 22q11.2DS patients present with CHD. SLC25A1 , which is found within the 22q11.2DS critical deletion region, encodes for the mitochondrial citrate carrier, a solute transporter localized to the inner mitochondrial membrane. In developing a knockout mouse model to study the in vivo functions of SLC25A1, we uncovered an unexpected perinatal-lethal phenotype that suggests roles for SLC25A1 in heart development. Hearts from 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 reveal that loss of Slc25a1 causes mitochondrial ultrastructural and functional defects. Lastly, transcriptomics analyses of metabolism-related genes revealed that Slc25a1 deletion causes widespread alterations in metabolic gene expression in a dosage-dependent manner. Our results highlight a novel role for SLC25A1 in cardiac morphogenesis and the transcriptional control of metabolic networks in the developing heart and point to a new role for SLC25A1 in the metabolic maturation of the developing myocardium.