IP3R2-mediated inter-organelle calcium signaling suppresses melanosome degradation

Organelle turnover is fundamental to cellular homeostasis and regulates both physiological processes and pathological outcomes. Skin pigmentation is determined by the balance between melanosome biogenesis and degradation. However, the mechanisms governing melanosome degradation, i.e., melanophagy remain largely unappreciated. Here, we reveal Inositol 1,4,5-trisphosphate receptor 2 (IP3R2) as a selective suppressor of melanophagy. To enable real-time monitoring of melanophagy, we developed and characterized two novel ratiometric live-cell imaging probes. Using a multi-pronged strategy combining live-cell imaging with the probes, biochemical studies, ultrastructural analyses, molecular approaches, and calcium imaging, we demonstrate that IP3R2 suppresses melanophagy. Importantly, in vivo studies in zebrafish model and meta-analysis of human skin microarrays substantiate the physiological relevance of IP3R2 in pigmentation. Mechanistically, IP3R2 depletion impairs mitochondrial Ca2+ uptake, elevates the ADP/ATP ratio and initiates melanophagy. Concurrently, IP3R2 loss enhances ER-lysosome contacts, increases lysosomal Ca2+ levels via TMEM165, and activates TRPML1 and nuclear translocation of TFEB. This in turn transcriptionally induces melanophagy receptor and E3 ligase. Collectively, IP3R2 acts as a critical determinant of melanophagy and a potential therapeutic target for pigmentary disorders and skin malignancies.