Lysosomal Ca2+ release-facilitated TFEB nuclear translocation alleviates ischemic brain injury by attenuating autophagic/lysosomal dysfunction in neurons
Neuronal death following ischemic stroke is often caused by dysfunction in autophagic/lysosomal processes, but the mechanisms to restore impaired autophagic flux remain unclear. Autophagic/lysosomal signaling can be enhanced when transcription factor EB (TFEB) translocates to the nucleus, a process that is facilitated by its dephosphorylation. A critical enzyme for TFEB dephosphorylation is calcineurin (CaN), whose activity is tightly regulated by cytosolic calcium ion concentrations ([Ca2+]), which in turn are controlled by the lysosomal Ca2+ channel-like protein TRPML1. Our research demonstrates that ML-SA1, a TRPML1 agonist, significantly enhances lysosomal Ca2+ release and increases CaN expression in neurons within the penumbra, promoting TFEB nuclear translocation and effectively reversing autophagic/lysosomal dysfunction. Furthermore, ML-SA1 treatment resulted in a significant reduction in neuronal loss, infarct size, and neurological deficits. In contrast, ML-SI3, an inhibitor of TRPML1, blocked lysosomal Ca2+ release, exacerbating autophagic flux impairment and worsening stroke-induced brain lesions. These findings suggest that elevating TRPML1 activity alleviates ischemic brain injury by restoring autophagic/lysosomal function through lysosomal Ca2+-mediated facilitation of TFEB nuclear translocation in neurons.