Sex-Specific Adaptations in Placental Mitochondrial Biogenesis and Function in babies Born with Critical Congenital Heart Disease

Congenital heart disease (CHD) is the leading cause of birth defects; most critical (c)CHD newborns will develop neurodevelopmental disorders. Abnormal placental development may be involved, as genetics explains only 30% of sporadic CHD cases. Growing evidence suggests that placental dysfunction may result in heart and brain defects, as it shares a common early development. We hypothesized that newborns with critical CHD exhibit sex-specific alterations in placental mitochondrial biogenesis and function which may affect the fetal growth trajectory. Term placenta and paired umbilical cord (UC) blood were collected at birth from cCHD (n=16) and matched control (n=20) neonates. Mitochondrial lipid complex (phosphatidic acid (PA), phosphatidylglycerol (PG), cardiolipin (CL)), acylcarnitine metabolites and organic acids were determined in placenta by LC-MS/MS. Gene expressions of enzymes involved in mitochondrial biogenesis, dynamics and lipid pathway were measured in placenta by RT-qPCR. Placental protein expressions of β-oxidation and OXPHOS were determined by Western Blot. Mitochondrial dynamics were reduced in cCHD placentas, particularly in male infants. Long-chain acylcarnitine (LC-acar) metabolites decreased in female cCHD placentas and increased in males, while they increased in both sexes in UC plasma. Malonate levels increased in cCHD placentas, affecting the TCA cycle. CL de novo synthesis was dysregulated in the cCHD placentas, though CL concentrations were similar in both groups. The cCHD placenta may compensate for cardiac defect in a potential sex-dependent manner, leading to an accumulation of LC-acylcarnitine in the UC plasma. Placental mitochondrial adaptation to metabolic needs may have a cardioprotective and neuroprotective effects.