Secretory pathway Ca 2+ -ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry

A complex interplay between the extracellular space, cytoplasm and individual organelles modulates Ca signaling to impact all aspects of cell fate and function. In recent years, the molecular machinery linking endoplasmic reticulum stores to plasma membrane Ca entry has been defined. However, the mechanism and pathophysiological relevance of store-independent modes of Ca entry remain poorly understood. Here, we describe how the secretory pathway Ca -ATPase SPCA2 promotes cell cycle progression and survival by activating store-independent Ca entry through plasma membrane Orai1 channels in mammary epithelial cells. Silencing SPCA2 expression or briefly removing extracellular Ca increased mitochondrial ROS production, DNA damage and activation of the ATM/ATR-p53 axis leading to G0/G1 phase cell cycle arrest and apoptosis. Consistent with these findings, SPCA2 knockdown confers redox stress and chemosensitivity to DNA damaging agents. Unexpectedly, SPCA2-mediated Ca entry into mitochondria is required for optimal cellular respiration and the generation of mitochondrial membrane potential. In hormone receptor positive (ER+/PR+) breast cancer subtypes, SPCA2 levels are high and correlate with poor survival prognosis. We suggest that elevated SPCA2 expression could drive pro-survival and chemotherapy resistance in cancer cells, and drugs that target store-independent Ca entry pathways may have therapeutic potential in treating cancer.