Melatonin Mitigates Acidosis-Induced Neuronal Damage by Up-Regulating Autophagy via the Transcription Factor EB

TL;DR

Melatonin protects neurons from acidosis by boosting autophagy through the movement of a key protein into the nucleus.

Contribution

Melatonin's neuroprotective mechanism via TFEB-mediated autophagy in acidosis is newly identified.

Findings

Acidosis reduces nuclear TFEB and suppresses autophagy, leading to neuronal damage.

Melatonin promotes TFEB nuclear translocation and enhances autophagy, reversing neuronal apoptosis.

Modulating TFEB confirms its role in melatonin's protective effects against acidosis.

Abstract

Acidosis, a common feature of cerebral ischemia and hypoxia, results in neuronal damage and death. This study aimed to investigate the protective effects and mechanisms of action of melatonin against acidosis-induced neuronal damage. SH-SY5Y cells were exposed to an acidic environment to simulate acidosis, and a photothrombotic (PT) infarction model was used to establish an animal model of cerebral ischemia of male C57/BL6J mice. Both in vivo and in vitro studies demonstrated that acidosis increased cytoplasmic transcription factor EB (TFEB) levels, reduced nuclear TFEB levels, and suppressed autophagy, as evidenced by elevated p62 levels, a higher LC3-II/LC3-I ratio, decreased synapse-associated proteins (PSD-95 and synaptophysin), and increased neuronal apoptosis. In contrast, melatonin promoted the nuclear translocation of TFEB, enhanced autophagy, and reversed neuronal apoptosis. Moreover, the role of TFEB in melatonin’s neuroprotective effects was validated by modulating TFEB nuclear translocation. In conclusion, melatonin mitigates acidosis-induced neuronal damage by promoting the nuclear translocation of TFEB, thereby enhancing autophagy. These findings offer new insights into potential treatments for acidosis.

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