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April 21st, 2025
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Capital Medical University
neuroscience
biorxiv

HIF-1α/STOML2 mediated PINK1-dependent mitophagy activation against hypoxia-induced neuronal injury

Li, Y.Open in Google Scholar•Guo, M.Open in Google Scholar•Tian, Z.Open in Google Scholar•Shao, Q.Open in Google Scholar•Liu, Y.Open in Google Scholar•Gu, Y.Open in Google Scholar•Xu, Z.Open in Google Scholar•Jin, F.Open in Google Scholar•Ji, X.Open in Google Scholar•Liu, J.Open in Google Scholar

Hypoxia contributes to brain disorders by causing neuronal injury. However, in the early stage of stress, neurons initiate a series of compensatory pathways to resist cell damage, but the underlying mechanisms have not been fully elucidated. In this study, we found that hypoxia transiently activates PTEN-induced kinase 1 (PINK1)-dependent mitophagy in the early stage before cell damage and neurological dysfunction. PINK1 overexpression protects neurons and it knockdown exacerbates neuronal damage, highlighting the key role of PINK1-dependent mitophagy in hypoxic adaptation. Mechanistically, hypoxia promotes HIF-1 nuclear translocation, inducing transcription of stomatin like 2 (STOML2). STOML2 relocates to the mitochondrial membrane, aiding phosphoglycerate mutase 5 (PGAM5) cleavage, which triggers PINK1-dependent mitophagy. Silencing HIF-1, STOML2, or PGAM5 inhibits PINK1-dependent mitophagy and worsens neurological function under hypoxia. Notably, intermittent hypoxia, a hypoxic conditioning strategy for improving hypoxic tolerance, enhances PINK1-dependent mitophagy by activating HIF-1/STOML2 axis, and protects neurons against hypoxia. In conclusion, our study reveals a new \"self-protection\" mechanism of neurons against hypoxic stress and discovers that intermittent hypoxia is a potential therapeutic strategy against hypoxia-induced injury.

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