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Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release

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  • Dongbiao Shen

    (Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University)

  • Xiang Wang

    (Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University)

  • Xinran Li

    (Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University)

  • Xiaoli Zhang

    (Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University)

  • Zepeng Yao

    (Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University)

  • Shannon Dibble

    (Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University)

  • Xian-ping Dong

    (Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University)

  • Ting Yu

    (University of Michigan Medical School)

  • Andrew P. Lieberman

    (University of Michigan Medical School)

  • Hollis D. Showalter

    (Vahlteich Medicinal Chemistry Core, University of Michigan)

  • Haoxing Xu

    (Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University)

Abstract

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.

Suggested Citation

  • Dongbiao Shen & Xiang Wang & Xinran Li & Xiaoli Zhang & Zepeng Yao & Shannon Dibble & Xian-ping Dong & Ting Yu & Andrew P. Lieberman & Hollis D. Showalter & Haoxing Xu, 2012. "Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release," Nature Communications, Nature, vol. 3(1), pages 1-11, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1735
    DOI: 10.1038/ncomms1735
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    Cited by:

    1. Yoshito Minami & Atsushi Hoshino & Yusuke Higuchi & Masahide Hamaguchi & Yusaku Kaneko & Yuhei Kirita & Shunta Taminishi & Toshiyuki Nishiji & Akiyuki Taruno & Michiaki Fukui & Zoltan Arany & Satoaki , 2023. "Liver lipophagy ameliorates nonalcoholic steatohepatitis through extracellular lipid secretion," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Flavia Giamogante & Lucia Barazzuol & Francesca Maiorca & Elena Poggio & Alessandra Esposito & Anna Masato & Gennaro Napolitano & Alessio Vagnoni & Tito Calì & Marisa Brini, 2024. "A SPLICS reporter reveals $${{{{{\boldsymbol{\alpha }}}}}}$$ α -synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Dengqin Zhong & Ruiyun Wang & Hongjing Zhang & Mengmeng Wang & Xuxia Zhang & Honghong Chen, 2023. "Induction of lysosomal exocytosis and biogenesis via TRPML1 activation for the treatment of uranium-induced nephrotoxicity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Kihyoun Park & Hyejin Lim & Jinyoung Kim & Yeseong Hwang & Yu Seol Lee & Soo Han Bae & Hyeongseok Kim & Hail Kim & Shin-Wook Kang & Joo Young Kim & Myung-Shik Lee, 2022. "Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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