Abstract
Aims:
Mitochondrial dysfunction is recognized as a central pathological mechanism in subarachnoid hemorrhage (SAH). This study aimed to investigate whether mitophagy serves as a key mechanism by which hydrogen (H2) exerts its antioxidative effects following SAH.
Results:
Using in vivo (mouse SAH model) and in vitro (HT22 cell SAH model) approaches, we demonstrated that H2 inhalation significantly improved neurological function and alleviated oxidative stress and apoptosis. Mechanistically, H2 maintained mitochondrial membrane potential and functional integrity by enhancing phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy. RNA sequencing and functional assays identified nuclear factor erythroid 2-related factor 2 (NRF2) as the key upstream target. H2 promoted NRF2 nuclear translocation and activated the antioxidant pathway. Dual-luciferase reporter assays further confirmed that NRF2 directly binds to and activates the PINK1 promoter. Pharmacological inhibition of NRF2 (ML385) or mitophagy (Mdivi-1) abolished the protective effects of H2, confirming that the NRF2-PINK1/Parkin axis is central to the effect of H2.
Innovation:
The present study clearly establishes the NRF2-PINK1/Parkin axis as a key mechanism underlying the neuroprotective effect of H2 in SAH. This study connects mitochondrial quality control with endogenous antioxidant systems, suggesting H2 administration as a potential mitochondrion-targeted clinical intervention.
Conclusion:
The NRF2-PINK1/Parkin axis is a novel and key mechanism underlying the neuroprotective effect of H2 in SAH. This finding advances our understanding beyond general antioxidant theories by demonstrating a specific, multistep molecular cascade. H2 administration is a potential mitochondrion-targeted intervention with strong implications for clinical translation in SAH patients. Antioxid. Redox Signal. 44, 443–463.
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