Maternal hyperglycemia-induced O-GlcNAcylation of CaMKIIδ promotes mtDNA release and cardiac remodeling in offspring.

Maternal diabetes during pregnancy increases the risk of metabolic and cardiac disorders in offspring. Nevertheless, the mechanism by which intrauterine hyperglycemia affects neonatal cardiac remodeling remains uncertain. This study aims to characterize the prenatal environment in the context of gestational diabetes mellitus and to identify the corresponding fetal changes. Using an intrauterine hyperglycemia rodent model, we observe cardiac remodeling and inflammatory responses in offspring hearts. Moreover, the O-GlcNAcylation levels are increased in neonatal hearts exposed to gestational diabetes. Further mechanistic investigations, supported by RNA sequencing and mitochondrial functional analyses, reveal that gestational diabetes triggers O-GlcNAcylation-dependent activation of CaMKIIδ during the embryonic stage. This activation leads to the release of mitochondrial DNA (mtDNA) from the mitochondrial matrix into the cytosol, which subsequently activates STING signaling and triggers an inflammatory response in neonatal cardiomyocytes. Pharmacological or genetic inhibition of O-GlcNAcylation attenuates mtDNA-induced myocardial inflammation and improves cardiac function in neonatal offspring subjected to intrauterine hyperglycemia. Together, these findings identify a previously unrecognized CaMKIIδ/mtDNA/STING axis in which CaMKIIδ O-GlcNAcylation leads to mtDNA-dependent activation of cardiac remodeling, suggesting that plasma mtDNA levels could serve as a predictive biomarker in neonatal cardiac inflammatory injury.