The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release
Open accessAbstract
Lysosomal lipid accumulation, defects in membrane trafficking and altered Ca2+ homoeostasis are common features in many lysosomal storage diseases. Mucolipin transient receptor potential channel 1 (TRPML1) is the principle Ca2+ channel in the lysosome. Here we show that TRPML1-mediated lysosomal Ca2+ release, measured using a genetically encoded Ca2+ indicator (GCaMP3) attached directly to TRPML1 and elicited by a potent membrane-permeable synthetic agonist, is dramatically reduced in Niemann–Pick (NP) disease cells. Sphingomyelins (SMs) are plasma membrane lipids that undergo sphingomyelinase (SMase)-mediated hydrolysis in the lysosomes of normal cells, but accumulate distinctively in lysosomes of NP cells. Patch-clamp analyses revealed that TRPML1 channel activity is inhibited by SMs, but potentiated by SMases. In NP-type C cells, increasing TRPML1's expression or activity was sufficient to correct the trafficking defects and reduce lysosome storage and cholesterol accumulation. We propose that abnormal accumulation of luminal lipids causes secondary lysosome storage by blocking TRPML1- and Ca2+-dependent lysosomal trafficking. Accumulation of lysosomal lipids is a feature of Niemann'-Picks (NP) disease, but how these lipids contribute to the disease is unclear. In this study, calcium released via the lysosomal TRPML1 channel is shown to be reduced in NP-type C cells, and sphingomyelins are found to inhibit the channel's activity.
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Cites
NAADP mobilizes calcium from acidic organelles through two-pore channels
Calcraft, P. J., Ruas, M., Pan, Z., Cheng, X., Arredouani, A., Hao, X., Tang, J., Rietdorf, K., Teboul, L., Chuang, K.-T., et al. (2009) · Nature · doi:10.1038/nature08030 · Cited by 760
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Self-citationBuratta, S., Tancini, B., Sagini, K., Delo, F., Chiaradia, E., Urbanelli, L., & Emiliani, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072576 · Cited by 446
Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases
Nixon, R. A., & Rubinsztein, D. C. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00757-5 · Cited by 435
A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation
Li, X., Rydzewski, N., Hider, A., Zhang, X., Yang, J., Wang, W., Gao, Q., Cheng, X., & Xu, H. (2016) · Nature Cell Biology · doi:10.1038/ncb3324 · Cited by 387
Self-citationMitochondria-lysosome contacts regulate mitochondrial Ca2+dynamics via lysosomal TRPML1
Peng, W., Wong, Y. C., & Krainc, D. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2003236117 · Cited by 336
Metadata
- Authors
- Shen, D., Wang, X., Li, X., Zhang, X., Yao, Z., Dibble, S., Dong, X.-P., Yu, T., Lieberman, A. P., Showalter, H. D., & Xu, H.
- Venue
- Nature Communications
- Published
- 2012-03-13
- Volume
- 3
- Issue
- 1
- Pages
- 731-731
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2065773869
- Cited by
- 495
- References
- 1
- FWCI
- 17.84
- Type
- journal article
- Language
- en
- Open access
- bronze
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