Maternal iron deficiency remodels cardiac mitochondria and alters stress responses in hypertensive pregnancy

Abstract

Maternal iron deficiency (ID) during pregnancy is associated with cardiovascular adaptations, including reduced blood pressure and improved cardiac efficiency in hypertensive pregnancy. However, whether these apparent functional gains are accompanied by preserved cardiac mitochondrial function remains unclear. Given the high metabolic demands of the maternal heart and irons central role in oxidative metabolism, we examined how maternal ID affects cardiac mitochondrial ultrastructure, respiration, dynamics, and redox status in pregnant spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Female SHR and WKY rats were fed iron-replete or iron-restricted diets before and throughout gestation. On gestational day 21, cardiac mitochondrial ultrastructure was assessed by transmission electron microscopy, respiration by high-resolution respirometry, mitochondrial dynamics and quality control proteins by immunoblotting, and antioxidant gene expression by RT-qPCR. Iron restriction reduced maternal hemoglobin levels in both strains. ID dams exhibited enlarged, morphologically heterogeneous mitochondria with reduced cristae density and lower succinate-supported respiration. SHR dams exhibited reduced fusion signalling, reflected by a lower L-OPA1:S-OPA1 ratio, lower MFN2 abundance, and further ID-associated reductions in MFN1 and MFN2. In contrast, DRP1 phosphorylation increased in ID-WKY dams. Iron restriction increased LC3-II:I ratio and BNIP3 in SHR, increased PINK1 in both strains, and increased antioxidant gene expression in ID-SHR but decreased in ID-WKY dams. Despite these alterations, downstream apoptosis activation was not observed. Maternal ID was associated with remodelling of myocardial mitochondrial ultrastructure and selectively constrains iron-dependent respiration in hypertensive pregnancy, suggesting favourable hemodynamic adaptations may coexist with underlying bioenergetic constraints in the maternal heart.