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 (IP 3 R2) 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 IP 3 R2 suppresses melanophagy. Importantly, in vivo studies in zebrafish model and meta-analysis of human skin microarrays substantiate the physiological relevance of IP 3 R2 in pigmentation. Mechanistically, IP 3 R2 depletion impairs mitochondrial Ca 2+ uptake, elevates the ADP/ATP ratio and initiates melanophagy. Concurrently, IP 3 R2 loss enhances ER–lysosome contacts, increases lysosomal Ca 2+ levels via TMEM165, and activates TRPML1 and nuclear translocation of TFEB. This in turn transcriptionally induces melanophagy receptor and E3 ligase. Collectively, IP 3 R2 acts as a critical determinant of melanophagy and a potential therapeutic target for pigmentary disorders and skin malignancies.