During mouse embryogenesis, cardiomyocytes undergo a metabolic switch from anaerobic glycolysis to aerobic (oxidative) metabolism, but this process remains unclear. Now, Mingjie Xu and colleagues identify an important regulator of this metabolic shift. The authors first profile the metabolic maturation of cardiomyocytes between E10.5 and E18.5. Using RNA-sequencing, and analysis of mitochondria ultrastructure and composition, they reveal a crucial period between E10.5 and E14.5 during which aerobic metabolism is activated. SRCAP complex components Znhit1, YL-1 and H2A.Z increase expression during this period of metabolic change, suggesting a role for SRCAP in oxidative metabolism. Indeed, cardiomyocyte-specific deletion of Znhit1, which disrupts SRCAP complex formation, causes abnormal mitochondrial morphology and mid-to-late stage heart development defects, such as ventricle dilation from E13.5. By comparing the transcriptomes of wild-type and Znhit1 mutant hearts, the researchers show that key mitochondrial function genes, such as those involved in fatty acid β-oxidation, are downregulated in the absence of Znhit1. Finally, CUT&Tag profiling shows that SRCAP directly regulates many key genes involved in these processes, such as Coq3 and Coq4, by binding to their promoters. These data provide new evidence for the SRCAP remodelling complex in activating oxidative metabolism during cardiomyocyte maturation.
