New connections: Flux and distance in Ca2+ signaling
Understanding ER-to-mitochondrial Ca2+ flux may provide ways to correct mitochondrial dysfunction in various diseases.The flow of Ca2+ from the endoplasmic reticulum (ER) to the mitochondria modulates mitochondrial bioenergetics and function and is affected by the distance between these two sets of organelles. A series of papers published in Science Signaling explore how ER-to-mitochondrial Ca2+ flux affects mitochondrial function and is affected by ER chaperones or disease. In normal cells, low-level, constitutive Ca2+ flow from the ER to the mitochondria supports the production of ATP through oxidative phosphorylation and therefore cellular proliferation. In this issue of Science Signaling, Cardenas et al. found that in cancer cells defective in oxidative phosphorylation, this interorganellar Ca2+ flow was critical for survival because it supported the generation of important metabolites through alternate metabolic pathways. In a paper in the Archives, Angebault et al. found that deficiency in the ER protein WFS1, which mimics the loss-of-function mutations that occur in Wolfram syndrome, was associated with decreased Ca2+ uptake by mitochondria, reduced mitochondrial contact with the ER, and decreased mitochondrial respiration due to the decreased abundance of the Ca2+ sensor NCS1. Reconstituting patient fibroblasts with NCS1 restored mitochondrial respiration and Ca2+ signaling dynamics. In a third paper in the Archives, Gutiérrez et al. found that the ER chaperone calnexin maintained SERCA, the ATPase that pumps Ca2+ into the ER, in a redox state that was optimal for activity. Mitochondria were closer to the ER in cells without calnexin than in cells with calnexin, an effect that enabled calnexin-deficient cells to partially rescue Ca2+ influx into mitochondria and to perform limited oxidative phosphorylation. In the final paper from the Archives, Kuo et al. found that loss of the ER cation channel PC2, which mimics loss-of-function mutations in an inherited form of polycystic kidney disease, led to enhanced tethering of mitochondria to the ER because of the increased abundance of the mitochondrial fusion factor MFN2. The increased mitochondria-ER association resulted in greater mitochondrial Ca2+ influx, respiration, and cellular proliferation, which in cultured cells and mouse models of polycystic kidney disease was rescued by deficiency in MFN2. These papers demonstrate that understanding the signaling pathways that regulate ER-to-mitochondrial Ca2+ flux may provide insights and potential therapeutic targets in diseases characterized by mitochondrial dysfunction due to abnormal flux or interorganellar distance.