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bioRxiv · 10.1101/2025.04.16.649120

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

Li, Y.·Guo, M.·Tian, Z.·Shao, Q.·Liu, Y.·Gu, Y.·Xu, Z.·Jin, F.·Ji, X.·Liu, J.
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Abstract

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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Li, Y., Guo, M., Tian, Z., Shao, Q., Liu, Y., Gu, Y., Xu, Z., Jin, F., Ji, X., Liu, J.. 2025-04-21. HIF-1α/STOML2 mediated PINK1-dependent mitophagy activation against hypoxia-induced neuronal injury. https://doi.org/10.1101/2025.04.16.649120

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