STIM1-Mitofusin2 interactions tether mitochondria and melanosome contacts that promote melanosome maturation

Mitochondria form contact sites with multiple organelles to coordinate diverse cellular processes. Melanosomes, lysosome-related organelles, undergo stepwise maturation to synthesize and store melanin, but how they interact with mitochondria remains unclear. Here we show that mitochondria-melanosome contacts dynamically increase during melanosome maturation and are mediated by STIM1-MFN2 interactions. Using a NanoBiT-based reporter system, MiMSBiT (Mitochondria-Melanosome contact reporter applying NanoBiT), to monitor reversible mitochondria-melanosome contacts in living cells, we demonstrate that STIM1 localizes to melanosomes and promotes their contact with mitochondrial MFN2. A transient decrease in melanosomal lumen calcium induces STIM1 clustering and enhances its association with MFN2. These contacts locally increase mitochondrial ATP availability, leading to melanosome lumen acidification via proton channel activation. This acidification facilitates PMEL fibrillation, a key step in melanosome maturation. Together, our findings reveal a mechanism by which mitochondria-melanosome contacts regulate melanosome maturation.