Secretory pathway Ca²⁺-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 Ca²⁺ signaling to impact all aspects of cell fate and function. In recent years, the molecular machinery linking endoplasmic reticulum stores to plasma membrane Ca²⁺ entry has been defined. However, the mechanism and pathophysiological relevance of store-independent modes of Ca²⁺ entry remain poorly understood. Here, we describe how the secretory pathway Ca²⁺-ATPase SPCA2 promotes cell cycle progression and survival by activating store-independent Ca²⁺ entry through plasma membrane Orai1 channels in mammary epithelial cells. Silencing SPCA2 expression or briefly removing extracellular Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ entry pathways may have therapeutic potential in treating cancer.