Placental dysregulation of mitochondrial morphology and dynamics as a hallmark of maternal age-related adaptation

Abstract

AIMS: Advanced maternal age (AMA), increasingly prevalent worldwide, is linked to obstetric risk even in clinically uncomplicated pregnancies. Mitochondria are essential for trophoblast metabolism and stress adaptation, and their alteration is associated with gestational pathologies. However, it remains unclear whether maternal age alone alters placental mitochondrial homeostasis. MATERIALS AND METHODS: Human placentas from AMA and control pregnancies were analysed by transmission electron microscopy (TEM) to assess mitochondrial ultrastructure and mitochondria-endoplasmic reticulum contacts (MERCs). Western blotting was used to evaluate regulators of mitochondrial fusion, fission, and mitophagy. KEY FINDINGS: placentas from AMA pregnancies showed a significant increase in mitochondrial number in both syncytiotrophoblast and cytotrophoblast cells, with regional variation between maternal and foetal sides. Despite increased abundance, mitochondria were smaller (reduced area and perimeter), indicating a fragmented phenotype, while circularity was unchanged. MERCs exhibited decreased distance and increased ER coverage, suggesting enhanced stress signaling and fission. Western blotting revealed decreased MFN1 with increased OPA1 and DRP1 expression, whereas MFN2, FIS1, and DNM2 remained unchanged. Mitophagy markers were dysregulated, with reduced OPTN and BNIP3 but elevated FUNDC1. SIGNIFICANCE: AMA is associated with fragmented and stress-adapted placental mitochondria, showing structural imbalance in dynamics and altered quality control even in the absence of clinical pathology. These features may reflect reduced placental capacity to buffer metabolic and stress challenges and contribute to increased vulnerability in pregnancies of older mothers, positioning mitochondria as a potential target for monitoring and improving outcomes in this population.