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Madreiter-Sokolowski, CT; Gottschalk, B; Sokolowski, AA; Malli, R; Graier, WF.
Dynamic Control of Mitochondrial Ca²⁺ Levels as a Survival Strategy of Cancer Cells.
Front Cell Dev Biol. 2021; 9:614668-614668 Doi: 10.3389/fcell.2021.614668 [OPEN ACCESS]
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Leading authors Med Uni Graz: Graier Wolfgang; Madreiter-Sokolowski Corina
Co-authors Med Uni Graz: Gottschalk Benjamin; Malli Roland; Sokolowski Armin
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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.
Find related publications in this database (Keywords): cancer cells; mitochondrial Ca2+ homeostasis; mitochondrial-ER interaction; uncoupling protein 2; ER stress