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dc.contributor.author
Madreiter-Sokolowski, Corina T.
dc.contributor.author
Gottschalk, Benjamin
dc.contributor.author
Sokolowski, Armin A.
dc.contributor.author
Malli, Roland
dc.contributor.author
Graier, Wolfgang F.
dc.date.accessioned
2021-03-02T07:48:22Z
dc.date.available
2021-03-02T03:54:04Z
dc.date.available
2021-03-02T07:48:22Z
dc.date.issued
2021-02-04
dc.identifier.issn
2296-634X
dc.identifier.other
10.3389/fcell.2021.614668
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/472321
dc.identifier.doi
10.3929/ethz-b-000472321
dc.description.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.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Frontiers Media
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
cancer cells
en_US
dc.subject
mitochondrial Ca2+ homeostasis
en_US
dc.subject
mitochondrial-ER interaction
en_US
dc.subject
uncoupling protein 2
en_US
dc.subject
ER stress
en_US
dc.title
Dynamic Control of Mitochondrial Ca2+ Levels as a Survival Strategy of Cancer Cells
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
ethz.journal.title
Frontiers in Cell and Developmental Biology
ethz.journal.volume
9
en_US
ethz.journal.abbreviated
Front. Cell Dev. Biol.
ethz.pages.start
614668
en_US
ethz.size
14 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Lausanne
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2021-03-02T03:54:17Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2021-03-02T07:48:32Z
ethz.rosetta.lastUpdated
2022-03-29T05:32:15Z
ethz.rosetta.versionExported
true
ethz.COinS
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