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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(2+) signaling to impact all aspects of cell fate and function. In recent years, the molecular machinery linking endoplasmic reticulum stores to plasma membrane Ca(2+) entry has been defined. However...

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Autores principales: Makena, Monish Ram, Ko, Myungjun, Mekile, Allatah X., Senoo, Nanami, Dang, Donna K., Warrington, John, Buckhaults, Phillip, Talbot, C. Conover, Claypool, Steven M., Rao, Rajini
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783100/
https://www.ncbi.nlm.nih.gov/pubmed/35063802
http://dx.doi.org/10.1016/j.redox.2022.102240
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author Makena, Monish Ram
Ko, Myungjun
Mekile, Allatah X.
Senoo, Nanami
Dang, Donna K.
Warrington, John
Buckhaults, Phillip
Talbot, C. Conover
Claypool, Steven M.
Rao, Rajini
author_facet Makena, Monish Ram
Ko, Myungjun
Mekile, Allatah X.
Senoo, Nanami
Dang, Donna K.
Warrington, John
Buckhaults, Phillip
Talbot, C. Conover
Claypool, Steven M.
Rao, Rajini
author_sort Makena, Monish Ram
collection PubMed
description A complex interplay between the extracellular space, cytoplasm and individual organelles modulates Ca(2+) signaling to impact all aspects of cell fate and function. In recent years, the molecular machinery linking endoplasmic reticulum stores to plasma membrane Ca(2+) entry has been defined. However, the mechanism and pathophysiological relevance of store-independent modes of Ca(2+) entry remain poorly understood. Here, we describe how the secretory pathway Ca(2+)-ATPase SPCA2 promotes cell cycle progression and survival by activating store-independent Ca(2+) entry through plasma membrane Orai1 channels in mammary epithelial cells. Silencing SPCA2 expression or briefly removing extracellular Ca(2+) 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(2+) 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(2+) entry pathways may have therapeutic potential in treating cancer.
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spelling pubmed-87831002022-01-28 Secretory pathway Ca(2+)-ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry Makena, Monish Ram Ko, Myungjun Mekile, Allatah X. Senoo, Nanami Dang, Donna K. Warrington, John Buckhaults, Phillip Talbot, C. Conover Claypool, Steven M. Rao, Rajini Redox Biol Research Paper A complex interplay between the extracellular space, cytoplasm and individual organelles modulates Ca(2+) signaling to impact all aspects of cell fate and function. In recent years, the molecular machinery linking endoplasmic reticulum stores to plasma membrane Ca(2+) entry has been defined. However, the mechanism and pathophysiological relevance of store-independent modes of Ca(2+) entry remain poorly understood. Here, we describe how the secretory pathway Ca(2+)-ATPase SPCA2 promotes cell cycle progression and survival by activating store-independent Ca(2+) entry through plasma membrane Orai1 channels in mammary epithelial cells. Silencing SPCA2 expression or briefly removing extracellular Ca(2+) 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(2+) 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(2+) entry pathways may have therapeutic potential in treating cancer. Elsevier 2022-01-17 /pmc/articles/PMC8783100/ /pubmed/35063802 http://dx.doi.org/10.1016/j.redox.2022.102240 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Makena, Monish Ram
Ko, Myungjun
Mekile, Allatah X.
Senoo, Nanami
Dang, Donna K.
Warrington, John
Buckhaults, Phillip
Talbot, C. Conover
Claypool, Steven M.
Rao, Rajini
Secretory pathway Ca(2+)-ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry
title Secretory pathway Ca(2+)-ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry
title_full Secretory pathway Ca(2+)-ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry
title_fullStr Secretory pathway Ca(2+)-ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry
title_full_unstemmed Secretory pathway Ca(2+)-ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry
title_short Secretory pathway Ca(2+)-ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry
title_sort secretory pathway ca(2+)-atpase spca2 regulates mitochondrial respiration and dna damage response through store-independent calcium entry
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783100/
https://www.ncbi.nlm.nih.gov/pubmed/35063802
http://dx.doi.org/10.1016/j.redox.2022.102240
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