Secretory pathway Ca2+-ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry

Redox Biol. 2022 Apr:50:102240. doi: 10.1016/j.redox.2022.102240. Epub 2022 Jan 17.


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.

Keywords: Ca(2+) signaling; DNA damage Response; Doxorubicin; ER+ breast cancer; Mitochondria; Oxygen consumption rate; ROS; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / metabolism
  • Calcium Signaling
  • Calcium* / metabolism
  • Calcium-Transporting ATPases / genetics*
  • Calcium-Transporting ATPases / metabolism
  • DNA Damage*
  • Female
  • Humans
  • Mitochondria* / genetics
  • Mitochondria* / metabolism
  • ORAI1 Protein / genetics
  • ORAI1 Protein / metabolism
  • Respiration
  • Secretory Pathway


  • ORAI1 Protein
  • Adenosine Triphosphatases
  • ATP2C2 protein, human
  • Calcium-Transporting ATPases
  • Calcium