IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-60349-5.html
   My bibliography  Save this article

Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux

Author

Listed:
  • Ran Chen

    (Danish Cancer Institute)

  • Bin Liu

    (Danish Cancer Institute
    Novo Nordisk)

  • Dawid Jaślan

    (Ludwig-Maximilians-Universität)

  • Lucija Kucej

    (Danish Cancer Institute)

  • Veronika Kudrina

    (Ludwig-Maximilians-Universität)

  • Belinda Warnke

    (Ludwig-Maximilians-Universität)

  • Yvonne E. Klingl

    (Ludwig-Maximilians-Universität)

  • Arnas Petrauskas

    (Ludwig-Maximilians-Universität)

  • Sandra Prat Castro

    (Ludwig-Maximilians-Universität)

  • Kenji Maeda

    (Danish Cancer Institute)

  • Christian Grimm

    (Ludwig-Maximilians-Universität
    Fraunhofer Institute for Translational Medicine and Pharmacology ITMP
    University of Oxford)

  • Marja Jäättelä

    (Danish Cancer Institute
    University of Copenhagen)

Abstract

The proper function of lysosomes depends on their ability to store and release calcium. While several lysosomal calcium release channels have been described, how lysosomes replenish their calcium stores in placental mammals has not been determined. Using genetic depletion and overexpression techniques combined with electrophysiology and visualization of subcellular ion concentrations and their fluxes across the lysosomal membrane, we show here that TMEM165 imports calcium to the lysosomal lumen and mediates calcium-induced lysosomal proton leakage. Accordingly, TMEM165 accelerates the recovery of cells from cytosolic calcium overload thereby enhancing cell survival while causing a significant acidification of the cytosol. These data indicate that in addition to its previously identified role in the glycosylation of proteins and lipids in the Golgi, a fraction of TMEM165 localizes on the lysosomal limiting membrane, where its putative calcium/proton antiporter activity plays an essential role in the regulation of intracellular ion homeostasis and cell survival.

Suggested Citation

  • Ran Chen & Bin Liu & Dawid Jaślan & Lucija Kucej & Veronika Kudrina & Belinda Warnke & Yvonne E. Klingl & Arnas Petrauskas & Sandra Prat Castro & Kenji Maeda & Christian Grimm & Marja Jäättelä, 2025. "Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60349-5
    DOI: 10.1038/s41467-025-60349-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-60349-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-60349-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Chen-Song Zhang & Simon A. Hawley & Yue Zong & Mengqi Li & Zhichao Wang & Alexander Gray & Teng Ma & Jiwen Cui & Jin-Wei Feng & Mingjiang Zhu & Yu-Qing Wu & Terytty Yang Li & Zhiyun Ye & Shu-Yong Lin , 2017. "Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK," Nature, Nature, vol. 548(7665), pages 112-116, August.
    2. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yingfeng Tu & Qin Yang & Min Tang & Li Gao & Yuanhao Wang & Jiuqiang Wang & Zhe Liu & Xiaoyu Li & Lejiao Mao & Rui zhen Jia & Yuan Wang & Tie-shan Tang & Pinglong Xu & Yan Liu & Lunzhi Dai & Da Jia, 2024. "TBC1D23 mediates Golgi-specific LKB1 signaling," Nature Communications, Nature, vol. 15(1), pages 1-21, 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. 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.
    4. Yanling Zhang & Yafei Cao & Xia Wu & Zhenghui Chen & Bowen Chen & Anhui Wang & Yanshen Guo & Wei Chen & Ruolan Xue & Zihua Liu & Yuanpei Li & Tian Li & Ruiqin Cheng & Ning Zhou & Jing Li & Yuan Liu & , 2024. "Thermal proteome profiling reveals fructose-1,6-bisphosphate as a phosphate donor to activate phosphoglycerate mutase 1," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Danielle L. Schmitt & Stephanie D. Curtis & Anne C. Lyons & Jin-fan Zhang & Mingyuan Chen & Catherine Y. He & Sohum Mehta & Reuben J. Shaw & Jin Zhang, 2022. "Spatial regulation of AMPK signaling revealed by a sensitive kinase activity reporter," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Javier Moral-Sanz & Sophronia A. Lewis & Sandy MacMillan & Marco Meloni & Heather McClafferty & Benoit Viollet & Marc Foretz & Jorge del-Pozo & A. Mark Evans, 2022. "AMPK deficiency in smooth muscles causes persistent pulmonary hypertension of the new-born and premature death," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Yaqiong Li & Zhipeng Niu & Jichao Yang & Xuke Yang & Yukun Chen & Yingying Li & Xiaohan Liang & Jingwen Zhang & Fuqiang Fan & Ping Wu & Chao Peng & Bang Shen, 2023. "Rapid metabolic reprogramming mediated by the AMP-activated protein kinase during the lytic cycle of Toxoplasma gondii," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    8. 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.
    9. Elizabeth Haythorne & Matthew Lloyd & John Walsby-Tickle & Andrei I. Tarasov & Jonas Sandbrink & Idoia Portillo & Raul Terron Exposito & Gregor Sachse & Malgorzata Cyranka & Maria Rohm & Patrik Rorsma, 2022. "Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    10. Zhenzhen Zi & Zhuzhen Zhang & Qiang Feng & Chiho Kim & Xu-Dong Wang & Philipp E. Scherer & Jinming Gao & Beth Levine & Yonghao Yu, 2022. "Quantitative phosphoproteomic analyses identify STK11IP as a lysosome-specific substrate of mTORC1 that regulates lysosomal acidification," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    11. 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.
    12. Kibum Kim & Hee Chan Yoo & Byung Gyu Kim & Sulhee Kim & Yulseung Sung & Ina Yoon & Ya Chun Yu & Seung Joon Park & Jong Hyun Kim & Kyungjae Myung & Kwang Yeon Hwang & Sunghoon Kim & Jung Min Han, 2022. "O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60349-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.