Lysosomal Ca²⁺ release-facilitated TFEB nuclear translocation alleviates ischemic brain injury by attenuating...

Neuronal death was frequently driven by autophagic/lysosomal dysfunction after ischemic stroke, whereas how to restore the impaired autophagic flux remained elusive. Autophagic/lysosomal signaling could be augmented after transcription factor EB (TFEB) nuclear translocation, which was facilitated by its dephosphorylation. A key TFEB dephosphorylase was calcineurin (CaN), whose activity was drastically regulated by cytosolic calcium ion concentration ([Ca²⁺]) controlled by lysosomal Ca²⁺ channel-like protein of TRPML1. Our research shows that ML-SA1, an agonist of the TRPML1 channel, significantly enhanced the lysosomal Ca²⁺ release and the CaN expression in penumbric neurons, subsequently promoted TFEB nuclear translocation, and greatly reversed autophagy/lysosome dysfunction. Moreover, ML-SA1 treatment significantly reduced neuronal loss, infarct size, and neurological deficits. By contrast, ML-SI3, an inhibitor of TRPML1, inhibited the lysosomal Ca²⁺ release conversely, aggravated the impairment of autophagic flux and consequentially exacerbated brain stroke lesion. These studies suggest that TRPML1 elevation alleviates ischemic brain injury by restoring autophagic/lysosomal dysfunction via Lysosomal Ca²⁺ release-facilitated TFEB nuclear translocation in neurons.