Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux
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...
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Nature Portfolio
2025-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60349-5 |
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| _version_ | 1849725071741943808 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ran Chen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a2e5fa8d2a1341f797638e58dbc4b81d |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a2e5fa8d2a1341f797638e58dbc4b81d2025-08-20T03:10:34ZengNature PortfolioNature Communications2041-17232025-06-0116111810.1038/s41467-025-60349-5Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ effluxRan Chen0Bin Liu1Dawid Jaślan2Lucija Kucej3Veronika Kudrina4Belinda Warnke5Yvonne E. Klingl6Arnas Petrauskas7Sandra Prat Castro8Kenji Maeda9Christian Grimm10Marja Jäättelä11Cell Death and Metabolism, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer InstituteCell Death and Metabolism, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer InstituteWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-UniversitätCell Death and Metabolism, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer InstituteWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-UniversitätWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-UniversitätWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-UniversitätWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-UniversitätWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-UniversitätCell Death and Metabolism, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer InstituteWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-UniversitätCell Death and Metabolism, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer InstituteAbstract 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.https://doi.org/10.1038/s41467-025-60349-5 |
| spellingShingle | 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 Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux Nature Communications |
| title | Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux |
| title_full | Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux |
| title_fullStr | Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux |
| title_full_unstemmed | Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux |
| title_short | Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux |
| title_sort | lysosomal tmem165 controls cellular ion homeostasis and survival by mediating lysosomal ca2 import and h efflux |
| url | https://doi.org/10.1038/s41467-025-60349-5 |
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