Dynamic Control of Mitochondrial Ca2+ Levels as a Survival Strategy of Cancer Cells

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Date
2021-02-04Type
- Journal Article
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Cited 12 times in
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Cited 13 times in
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Abstract
Cancer cells have increased energy requirements due to their enhanced proliferation activity. This energy demand is, among others, met by mitochondrial ATP production. Since the second messenger Ca2+ maintains the activity of Krebs cycle dehydrogenases that fuel mitochondrial respiration, proper mitochondrial Ca2+ uptake is crucial for a cancer cell survival. However, a mitochondrial Ca2+ overload induces mitochondrial dysfunction and, ultimately, apoptotic cell death. Because of the vital importance of balancing mitochondrial Ca2+ levels, a highly sophisticated machinery of multiple proteins manages mitochondrial Ca2+ homeostasis. Notably, mitochondria sequester Ca2+ preferentially at the interaction sites between mitochondria and the endoplasmic reticulum (ER), the largest internal Ca2+ store, thus, pointing to mitochondrial-associated membranes (MAMs) as crucial hubs between cancer prosperity and cell death. To investigate potential regulatory mechanisms of the mitochondrial Ca2+ uptake routes in cancer cells, we modulated mitochondria–ER tethering and the expression of UCP2 and analyzed mitochondrial Ca2+ homeostasis under the various conditions. Hence, the expression of contributors to mitochondrial Ca2+ regulation machinery was quantified by qRT-PCR. We further used data from The Cancer Genome Atlas (TCGA) to correlate these in vitro findings with expression patterns in human breast invasive cancer and human prostate adenocarcinoma. ER-mitochondrial linkage was found to support a mitochondrial Ca2+ uptake route dependent on uncoupling protein 2 (UCP2) in cancer cells. Notably, combined overexpression of Rab32, a protein kinase A-anchoring protein fostering the ER-mitochondrial tethering, and UCP2 caused a significant drop in cancer cells' viability. Artificially enhanced ER-mitochondrial tethering further initiated a sudden decline in the expression of UCP2, probably as an adaptive response to avoid mitochondrial Ca2+ overload. Besides, TCGA analysis revealed an inverse expression correlation between proteins stabilizing mitochondrial-ER linkage and UCP2 in tissues of human breast invasive cancer and prostate adenocarcinoma. Based on these results, we assume that cancer cells successfully manage mitochondrial Ca2+ uptake to stimulate Ca2+-dependent mitochondrial metabolism while avoiding Ca2+-triggered cell death by fine-tuning ER-mitochondrial tethering and the expression of UCP2 in an inversed manner. Disruption of this equilibrium yields cancer cell death and may serve as a treatment strategy to specifically kill cancer cells. © Copyright © 2021 Madreiter-Sokolowski, Gottschalk, Sokolowski, Malli and Graier. Show more
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https://doi.org/10.3929/ethz-b-000472321Publication status
publishedExternal links
Journal / series
Frontiers in Cell and Developmental BiologyVolume
Pages / Article No.
Publisher
Frontiers MediaSubject
cancer cells; mitochondrial Ca2+ homeostasis; mitochondrial-ER interaction; uncoupling protein 2; ER stressMore
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Citations
Cited 12 times in
Web of Science
Cited 13 times in
Scopus
ETH Bibliography
yes
Altmetrics