Mitochondrial dysfunction in placental ischemic diseases: Mechanisms and therapeutic implications

Placental ischemic diseases, including preeclampsia (PE) and intrauterine growth restriction (IUGR), are leading causes of maternal and neonatal morbidity and mortality worldwide. These conditions originate from defective spiral artery remodeling, leading to reduced uteroplacental perfusion and chronic placental ischemia. The resultant hypoxia/reoxygenation injury creates a hostile environment that profoundly impacts placental cellular function. Central to this dysfunction is the mitochondrion, an organelle critical for energy production, calcium homeostasis, and the regulation of apoptosis. Emerging evidence positions mitochondrial dysfunction as a key nexus in the pathophysiology of placental ischemia. This review synthesizes current knowledge on the mechanisms driving mitochondrial impairment in the ischemic placenta. We explore the role of oxidative stress, the opening of the mitochondrial permeability transition pore (mPTP), disrupted mitochondrial dynamics (fusion/fission), and subsequent activation of apoptotic and inflammatory cascades. Furthermore, we discuss the potential of mitochondrial-targeted therapeutics, such as specific antioxidants and inhibitors of the mPTP, as novel strategies to alleviate placental damage and improve pregnancy outcomes. A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science to identify relevant preclinical studies and mechanistic insights, which were synthesized narratively. Understanding these intricate mitochondrial pathways is crucial for developing effective interventions for these devastating disorders.