Polycystin 2 regulates mitochondrial Ca 2+ signaling, bioenergetics, and dynamics through mitofusin 2
| العنوان: | Polycystin 2 regulates mitochondrial Ca 2+ signaling, bioenergetics, and dynamics through mitofusin 2 |
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| المؤلفون: | Jeffrey L. Falcone, David L. Kaplan, Fernanda O. Lemos, Allison L. Brill, Ivana Y. Kuo, Jason Y. Jiang, Ke Dong, Darren P. Wallace, Yiqiang Cai, Aldebaran M. Hofer, Barbara E. Ehrlich, Erica P. Kimmerling |
| المصدر: | Science Signaling. 12 |
| بيانات النشر: | American Association for the Advancement of Science (AAAS), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | endocrine system, 0303 health sciences, Gene knockdown, education.field_of_study, Chemistry, Endoplasmic reticulum, MFN2, Cell Biology, Mitochondrion, Biochemistry, Cell biology, 03 medical and health sciences, Mitofusin-2, 0302 clinical medicine, Polycystin 2, Mitochondrial biogenesis, 030220 oncology & carcinogenesis, Signal transduction, education, Molecular Biology, 030304 developmental biology |
| الوصف: | Mitochondria and the endoplasmic reticulum (ER) have an intimate functional relationship due to tethering proteins that bring their membranes in close (~30 nm) apposition. One function of this interorganellar junction is to increase the efficiency of Ca2+ transfer into mitochondria, thus stimulating mitochondrial respiration. Here, we showed that the ER cation-permeant channel polycystin 2 (PC2) functions to reduce mitochondria-ER contacts. In cell culture models, PC2 knockdown led to a 50% increase in mitofusin 2 (MFN2) expression, an outer mitochondrial membrane GTPase. Live-cell super-resolution and electron microscopy analyses revealed enhanced MFN2-dependent tethering between the ER and mitochondria in PC2 knockdown cells. PC2 knockdown also led to increased ER-mediated mitochondrial Ca2+ signaling, bioenergetic activation, and mitochondrial density. Mutation or deletion of the gene encoding for PC2 results in autosomal dominant polycystic kidney disease (ADPKD), a condition characterized by numerous fluid-filled cysts. In cell culture models and mice with kidney-specific PC2 knockout, knockdown of MFN2 rescued defective mitochondrial Ca2+ transfer and diminished cell proliferation in kidney cysts. Consistent with these results, cyst-lining epithelial cells from human ADPKD kidneys had a twofold increase in mitochondria and MFN2 expression. Our data suggest that PC2 normally serves to limit key mitochondrial proteins at the ER-mitochondrial interface and acts as a checkpoint for mitochondrial biogenesis and bioenergetics. Loss of this regulation may contribute to the increased oxidative metabolism and aberrant cell proliferation typical of kidney cysts in ADPKD. |
| تدمد: | 1937-9145 1945-0877 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::893f4ab0ff8b1ba21ad50cb26110f2afTest https://doi.org/10.1126/scisignal.aat7397Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi...........893f4ab0ff8b1ba21ad50cb26110f2af |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19379145 19450877 |
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