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Sci Signal. 2019 May 7;12(580). pii: eaat7397. doi: 10.1126/scisignal.aat7397.

Polycystin 2 regulates mitochondrial Ca2+ signaling, bioenergetics, and dynamics through mitofusin 2.

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Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
Department of Surgery, Harvard Medical School, Brigham and Women's Hospital, MA 02132, USA.
VA Boston Healthcare System, West Roxbury, MA 02132, USA.
Department of Biomedical Engineering, Tufts University. Medford, MA 02155, USA.
Department of Internal Medicine, Yale University School of Medicine. New Haven, CT 06510, USA.
Department of Medicine and the Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, USA.


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.


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