Abstract
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.
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Data availability
The mass spectrometry proteomics data generated in this study have been deposited in the ProteomeXchange Consortium via the jPOST partner repository under the dataset identifiers JPST003803 and PXD063939. Source data underlying all figures are provided with this paper. Other data supporting the findings of this study are available from the corresponding authors. Source data are provided with this paper.
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Acknowledgements
We thank Michael S. Marks for the generous gift of PMEL fibril (I51) antibody. We thank Saki Asada for technical assistance. This study was partially supported by the MEXT/JSPS KAKENHI [Grant Nos. 22K15399, 22H05574, 24H01327, and 24K18382 (for IS), 23K14185 and 22K20637 (for NI), 21K06844 (for RI), 23K02691, 20H04911 and 20H03454 (for SY)], the Uehara Memorial Foundation (for IS and SY), the Kowa Life Science Foundation (to IS)], the Takeda Science Foundation (2025) (for SY), the Daiichi Sankyo Foundation of Life Science (for SY) and AMED [Grant No. JP20gm5010002 and JP25gm2110001 (to SY)].
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I.S. and S.Y. designed the experiments; I.S., N.I., K.U., Y.A., H.O., Y.I., and F.Y. performed the experiments; I.S. and S.Y. analyzed and interpreted the data; Y.M., H.A., S.N., Y.A., K.N., Y.H., and R.I. assisted in the analysis; I.S. and S.Y. wrote the paper.
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Shiiba, I., Ishikawa, Y., Oshio, H. et al. STIM1-Mitofusin2 interactions tether mitochondria and melanosome contacts that promote melanosome maturation. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70282-w
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DOI: https://doi.org/10.1038/s41467-026-70282-w
