Ohanele, C. | bioRxiv Science

bioRxiv2026

Cardiomyocyte-intrinsic SLC25A1 regulates cardiac differentiation and mitochondrial function

Cardiac morphogenesis is an intricate process that requires a precise coordination between metabolic and structural maturation, but how these processes are linked remain unclear. In previous work, we identified one candidate underlying this connection: the mitochondrial citrate carrier (SLC25A1), a critical regulator of embryonic heart development. Here, using systemic and cardiomyocyte-specific Slc25a1 deletion in mice together with SLC25A1 knockout (KO) human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we demonstrate that SLC25A1 functions cell-autonomously within cardiomyocytes to regulate differentiation, mitochondrial maturation, and ventricular morphogenesis. Transcriptomic analysis of SLC25A1-deficient hearts revealed dysregulation of gene programs regulating cardiomyocyte differentiation and mitochondrial function. Consistent with these changes, loss of SLC25A1 in developing cardiomyocytes impaired mitochondrial function and resulted in defective ventricular wall compaction in vivo. Likewise, SLC25A1 KO hiPSC-CMs exhibited defective cardiomyocyte differentiation, disorganized myofibrils, and immature mitochondrial organization and function in vitro. Together, our findings position SLC25A1 as a cardiomyocyte-intrinsic, cell-autonomous regulator that links mitochondrial citrate export to developmental gene programs, revealing a mitochondrial regulatory axis for cardiomyocyte maturation and cardiac morphogenesis that contributes to congenital heart disease.

developmental biology↗

bioRxiv2023

Mitochondrial citrate carrier SLC25A1 is a dosage-dependent regulator of metabolic reprogramming and morphogenesis in the developing heart

The developing mammalian heart undergoes an important metabolic shift from glycolysis toward mitochondrial oxidation, such that oxidative phosphorylation defects may present with cardiac abnormalities. Here, we describe a new mechanistic link between mitochondria and cardiac morphogenesis, uncovered by studying mice with systemic loss of the mitochondrial citrate carrier SLC25A1. Slc25a1 null embryos displayed impaired growth, cardiac malformations, and aberrant mitochondrial function. Importantly, Slc25a1 heterozygous embryos, which are overtly indistinguishable from wild type, exhibited an increased frequency of these defects, suggesting Slc25a1 haploinsuffiency and dose-dependent effects. Supporting clinical relevance, we found a near-significant association between ultrarare human pathogenic SLC25A1 variants and pediatric congenital heart disease. Mechanistically, SLC25A1 may link mitochondria to transcriptional regulation of metabolism through epigenetic control of gene expression to promote metabolic remodeling in the developing heart. Collectively, this work positions SLC25A1 as a novel mitochondrial regulator of ventricular morphogenesis and cardiac metabolic maturation and suggests a role in congenital heart disease.

developmental biology↗