Abstract
Hypoxic stress contributes to brain disorders by causing neuronal injury, making it crucial to understand neuronal hypoxic response mechanisms for disease resistance. 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. When PINK1-dependent mitophagy is inhibited, neuronal injury begins to exacerbate. Under hypoxia, overexpression of PINK1 can resist neuronal injury, while knockdown of PINK1 aggravates neuronal injury, revealing that PINK1-dependent mitophagy plays a key role in neuronal compensatory hypoxia response. Mechanistically, in the early stage of hypoxia, the nuclear translocation of HIF-1α increases, mediating the transcription of its downstream target molecule STOML2. STOML2 translocates to the outer mitochondrial membrane and participates in the cleavage of PGAM5. These processes initiate PINK1-dependent mitophagy. Knockdown of HIF-1α, STOML2, or PGAM5 inhibits mitophagy and worsens hypoxia-induced dysfunction, highlighting this pathway’s importance. Intermittent hypoxia, a conditioning strategy, stimulates endogenous protection. Notably, it activates the HIF-1α/STOML2 axis, inducing PINK1-dependent mitophagy and protecting neurons. In conclusion, our study reveals a new “self-protection” mechanism of neurons against hypoxic stress and discovers that intermittent hypoxia can effectively activate this pathway to resist neuronal injury, providing new insights into the mechanisms and interventions of hypoxia-related nerve injury.
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The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
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Funding
This research was supported by the National Natural Science Foundation of China (Grant number: 32100925, 82571493), National Scientific and Technological Innovation 2030 of China-Major project (2023ZD0505300, 2023ZD0505304), Outstanding Youth Project of Capital Medical University (Grant number: B2403), the Beijing Nova Program (Grant number: 20230484436), the Chinese Institutes for Medical Research (Grant number: CX23YQ01) and Beijing-Tianjin-Hebei Basic Research Cooperation Project, No. 22JCZXJC00190.
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Yuning Li performed most of the experiments in this study and drafted the majority of the manuscript content; Zirui Xu contributed to the experiments and undertook the revision of the manuscript; Zhengming Tian undertook the revision of the manuscript and helped to analyze the study data; Yakun Gu investigated the experiments process; Yingxia Liu helped design the methodology; Feiyang Jin contributed to the experiments; Mengyuan Guo participated in the experiments and helped write the manuscript; Qianqian Shao provided the materials, animals; Xunming Ji contributed to the development of experimental ideas; Jia Liu designed the experiments and supervise the research activity execution.
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Li, Y., Xu, Z., Tian, Z. et al. Novel mechanism of neuronal hypoxia response: HIF-1α/STOML2 mediated PINK1-dependent mitophagy activation against neuronal injury. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-02960-z
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DOI: https://doi.org/10.1038/s41420-026-02960-z
