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

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Science Signaling  07 May 2019:
Vol. 12, Issue 580, eaat7397
DOI: 10.1126/scisignal.aat7397

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PC2 separates mitochondria from the ER

Patients with loss-of-function mutations in polycystin (PC) 1 or 2 develop fluid-filled cysts due to excessive proliferation of kidney epithelial cells. Kuo et al. found that loss of the ER cation channel PC2 led to increased abundance of the mitochondrial fusion factor MFN2 and enhanced tethering of mitochondria to the ER. The increased mitochondria-ER association resulted in greater mitochondrial Ca2+ influx, biogenesis, and respiration and cellular proliferation, which in cultured cells and mouse models of polycystic kidney disease was rescued by deficiency in MFN2. These results show that PC2 acts to restrict mitochondrial tethering to the ER in kidney cells to prevent inappropriate Ca2+-dependent increases in mitochondrial function and cellular proliferation.


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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