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

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.