Interactions between the endoplasmic reticulum (ER) and mitochondria occur at the mitochondria-associated ER membrane (MAM). This region regulates mitochondrial metabolism, in part through the transfer of Ca2+ from the ER to mitochondria. Researchers now demonstrate that polycystin 2 (PC2) modulates proteins at the MAM to regulate Ca2+ signalling and mitochondrial dynamics. “Our results show that PC2 has profound effects on cell metabolism through a Ca2+-dependent mitochondrial process,” says Barbara Ehrlich.
Loss-of-function mutations in the genes that encode the polycystins PC1 and PC2 result in autosomal dominant polycystic kidney disease (ADPKD). Previous research suggested that cyst development is associated with metabolic changes; however, the role of PC2 in this process was unclear. “The fact that PC2 resides at a location in the ER membrane that enables it to potentially modulate mitochondrial metabolism led us to hypothesize that PC2-regulated changes in Ca2+ signalling might alter mitochondrial function,” says Ehrlich. Using cell lines, Ivana Kuo, Allison Brill and colleagues show that knockdown (KD) of PC2 enhances ER-mediated mitochondrial Ca2+ influx. This influx was associated with increased tethering of the ER to mitochondria and increased expression of the mitochondrial tethering protein MFN2. Mitochondria of PC2-KD cells also exhibited increased metabolic activity and reduced movement, indicative of prolonged interaction between mitochondria and the ER.
Similar to PC2-KD cells, cystic renal cells of PC2-knockout mice had increased MFN2 levels and enhanced mitochondrial Ca2+ influx. KD of MFN2 in the kidneys of these mice restored mitochondrial Ca2+ to control levels and reduced proliferation in kidney cysts. Finally, cyst-lining cells from human patients with ADPKD also demonstrated increased MFN2 expression. “We are incredibly excited by our finding that targeting the connections between the ER and mitochondria to reduce Ca2+ transfer decreases cell proliferation in our cystic mouse models,” says Ehrlich. “Allison Brill is now investigating how PC2 and its downstream signalling partners could be targeted to modulate mitochondrial function,” she adds.
Kuo, I. Y. et al. Polycystin 2 regulates mitochondrial Ca2+ signaling, bioenergetics, and dynamics through mitofusin 2. Sci. Signal. 12, eaat7397 (2019)
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Allison, S.J. PC2–mitochondria interactions in PKD. Nat Rev Nephrol 15, 458 (2019). https://doi.org/10.1038/s41581-019-0162-3