Hypoxia ischemia (HI) is a leading cause of cerebral palsy and long-term neurological sequelae in infants. Given that mitochondrial dysfunction in neurons contributes to HI brain damage, this study aimed to investigate the regulatory role of miR-9-5p in mitochondrial function following HI injury.
Results:
Overexpression of miR-9-5p in HI mice or H2O2-exposed PC12 cells suppressed neuronal injury, associated with increased mitochondrial copy number, normalizing mitochondrial membrane potential, improved nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activation, and downregulation of Keap1. This was mediated, in part, through the ability of this miR-9-5p to bind and regulate the transcriptional activity of zinc finger and BTB domain-containing protein 20 (ZBTB20). Further study suggested that the knockdown of ZBTB20 exerts neuroprotection by inhibiting Nrf2/Keap1 interaction to promote the translocation of Nrf2 from the cytoplasm to the nucleus and the consequent expression of antioxidant proteins. Notably, the protective effects of miR-9-5p overexpression against HI-induced mitochondrial damage were reversed by the Nrf2 inhibitor ML385. Finally, the utilization of liposomes for the delivery of miR-9-5p (miR-9-5p@Lip) presents a promising therapeutic strategy for the treatment of HI injury.
Innovation:
miR-9-5p is a potential therapeutic agent for ischemic stroke through its modulation of the ZBTB20/Nrf2/Keap1 signaling pathway, influencing mitochondrial function and antioxidant response. Furthermore, the use of liposomal delivery for miR-9-5p offers a promising therapeutic strategy for HI injury.
Conclusion:
Overexpression of miR-9-5p protects against cerebral HI injury by modulating mitochondrial function through the ZBTB20/Nrf2/Keap1 signaling pathway. Antioxid. Redox Signal. 42, 512–528.
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