Work

Novel mechanism of neuronal hypoxia response: HIF-1α/STOML2 mediated PINK1-dependent mitophagy activation against neuronal injury

Year: 2026

Type: article

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.

Source: Cell Death Discovery

DOI: 10.1038/s41420-026-02960-z