The Role of SLC25A1 in the Regulation of Embryonic Cardiac Development Restricted; Files & ToC
Ohanele, Chiemela (Summer 2026)
Abstract
The developing heart is a metabolically complex environment that undergoes important physiological and morphological transitions before birth. The early embryonic heart is heavily dependent upon glycolysis to meet its energetic demands; as mitochondria and their metabolic processes mature, the late-stage embryonic heart becomes more reliant upon oxidative phosphorylation and lipid metabolism. SLC25A1, the mitochondrial citrate carrier, exports mitochondrial citrate to the cytosol, and is required for the generation of acetyl-CoA and regulation of metabolic processes such as lipid metabolism and glycolysis. We have found that systemic loss of SLC25A1 leads to defects in cardiac morphogenesis, mitochondrial ultrastructure and function, and dysregulation of metabolic gene expression. Loss of SLC25A1 in the developing heart also leads to immature metabolic profiles, where hearts are less reliant upon oxidative phosphorylation and are predicted to have higher rates of glycolysis. Furthermore, we found that metabolic reprogramming is driven by SLC25A1-dependent histone acetylation at metabolic gene loci. As our first study explores the effect of systemic SLC25A1 deletion, we investigated whether SLC25A1 effects are cardiomyocyte intrinsic. Here we found that cardiomyocyte-specific deletion induces defects in mitochondrial function both in vivo and in vitro. Interestingly, as SLC25A1 links mitochondrial metabolism to cellular programs required for cardiac development and morphogenesis, we found that SLC25A1 deletion in hiPSC-derived cardiomyocytes leads to differentiation and maturation defects. Lastly, as our studies position mitochondrial function as a critical parameter of proper cardiac development, we developed a novel technique to assess respiration using a fluorescence-based plate reader assay. Together, this thesis comprehensively evaluates the link between metabolic intermediates and gene regulation required for cardiac development, while providing potential mechanisms underlying the development of congenital heart disease.
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File download under embargo until 20 August 2027 | 2026-06-23 19:50:21 -0400 | File download under embargo until 20 August 2027 |
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