Fig 9

IP₃R2 regulates melanophagy via inter-organelle Ca²⁺ dynamics.
Schematic model illustrating the role of IP₃R2-mediated Ca²⁺ signaling in regulating melanophagy. In wild-type melanocytes, αMSH–MC1R–IP₃ signaling activates IP₃R2, facilitating ER–mitochondrial Ca²⁺ transfer and mitochondrial ATP production. Lysosomal pH homeostasis limits excessive TRPML1-dependent Ca²⁺ release, keeping TFEB largely cytosolic, thereby leading to basal melanophagy. IP₃R2 knockdown disrupts mitochondrial Ca²⁺ uptake, induces energy stress and activates AMPK–ULK1 signaling, which supports melanophagy. The increased proximity of the lysosome to the ER and Ca²⁺ release through ER leak channels elevates lysosomal Ca²⁺ levels. The lowered lysosomal pH facilitates TRPML1-mediated Ca²⁺ efflux, which dephosphorylates TFEB, promoting its nuclear translocation, transcription of melanophagy regulators (RCHY1 and OPTN), increased melanophagy, and thereby reduced pigmentation. Created in BioRender. Motiani, R. (2026) https://BioRender.com/h5bus03.