Targeting mitochondrial oxidative stress to protect against preterm birth and fetal brain injury via Nrf2 induction.

AIMS: Preterm birth, recognized as delivery before 37 weeks of gestation, is a multifactorial syndrome characterizing as the main cause of neonatal mortality. Reactive oxygen species (ROS) have been identified as proinflammatory factors to cause placental inflammation, thereby resulting in several pregnancy outcomes. To date, limited knowledge regarding the underlying mechanisms of ROS-induced preterm birth has been reported. Here, we aimed to investigate the role of oxidative stress in preterm birth and the protective effects of mitochondria-targeted antioxidant MitoTEMPO (MT) on preterm labor and offspring mice.

RESULTS: Here, we found that preterm placentas had abnormal mitochondrial function, oxidative stress and inflammatory response. In the LPS-induced preterm birth mouse model, MT inhibited preterm birth by ameliorating maternal oxidative stress and inflammation, especially in placentas, thus improving placental function to maintain pregnancy. Antenatal administration of MT prevented LPS-induced fetal brain damage in acute phase and improved long-term neurodevelopmental impairments. Furthermore, our in vitro investigations validated that MT retarded the ROS accumulation and inflammatory response in LPS-stimulated trophoblast cells by promoting Keap1 degradation and subsequently activating Nrf2. By inhibiting Nrf2 activation, we discovered that the anti-inflammation and protective characteristics of MT were Nrf2/ARE pathway-dependent.

INNOVATION AND CONCLUSION: MT inhibited preterm birth and fetal brain injury by inhibiting maternal inflammation and improving placental function through Keap1/Nrf2/ARE signaling pathway. Our findings provide a novel therapeutic strategy for preterm birth.