Cardiomyocyte-intrinsic SLC25A1 regulates cardiac differentiation and mitochondrial function

Area of Science:

• Cardiovascular Biology
• Mitochondrial Metabolism
• Developmental Biology

Background:

• Cardiac morphogenesis requires coordinated metabolic and structural maturation.
• The mitochondrial citrate carrier (SLC25A1) was previously identified as a key regulator of embryonic heart development.

Purpose of the Study:

• To investigate the cell-autonomous role of SLC25A1 in cardiomyocyte differentiation, mitochondrial maturation, and ventricular morphogenesis.
• To elucidate the molecular mechanisms linking SLC25A1 function to cardiac development.

Main Methods:

• Systemic and cardiomyocyte-specific Slc25a1 deletion in mice.
• SLC25A1 knockout (KO) in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
• Transcriptomic analysis of SLC25A1-deficient hearts.
• In vivo and in vitro assessments of cardiomyocyte function and mitochondrial health.

Main Results:

• SLC25A1 loss impairs cardiomyocyte differentiation, mitochondrial function, and myofibril organization.
• Defective ventricular wall compaction observed in vivo.
• Transcriptomic analysis revealed dysregulated gene programs related to cardiomyocyte differentiation and mitochondrial function.

Conclusions:

• SLC25A1 acts cell-autonomously within cardiomyocytes to regulate cardiac development.
• SLC25A1 links mitochondrial citrate export to developmental gene programs.
• A mitochondrial regulatory axis involving SLC25A1 is critical for cardiomyocyte maturation and cardiac morphogenesis, offering insights into congenital heart disease.