Medizinische Universität Graz - Research portal
Selected Publication:
Schlick, K.
Rewiring of mitochondrial Ca2+ by T3 affecting metabolism and proliferation of breast cancer cells.
[ Diplomarbeit/Master Thesis (FH) ] TU Graz; 2023. pp.79.
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- Authors Med Uni Graz:
- Advisor:
- Madreiter-Sokolowski Corina
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- Abstract:
- Thyroid hormones are crucial regulators of cell metabolism and impact various processes, including mitochondrial function. The biologically active triiodothyronine (T3) can interfere with multiple intracellular pathways, such as Ca2+ signaling, by altering gene expression. Ca2+ ions affect mitochondrial energy metabolism, as they are required for the activity of specific dehydrogenases involved in the tricarboxylic acid cycle. Notably, T3 can boost mitochondrial metabolism in HeLa cells by facilitating the mitochondrial Ca2+ uniporter (MCU) complex-mediated Ca2+ uptake, resulting in enhanced ATP and ROS production. In the current study, we tested whether the T3-sensitivity of different cancer cells is dependent on mitochondrial Ca2+ remodeling. Consequently, we investigated the T3-induced signaling in T3-sensitive human breast cancer cell line MCF7 and in T3-insensitive human prostate carcinoma cell line PC3. After treating MCF7 with T3 for 3 h, fluorescence live cell imaging revealed a significant increase of mitochondrial Ca2+ ([Ca2+]mito) uptake, while [Ca2+]mito uptake remained unchanged in PC3 cells. The enhanced [Ca2+]mito uptake correlated with our results of the mitochondrial ATP ([ATP]mito) assessment, indicating a T3-dependent boost of mitochondrial energy metabolism in MCF7. Our results imply that the elevated metabolic activity in response to T3 is mediated by the [Ca2+]mito uptake machinery since an inhibition of MCU or the uncoupling proteins (UCP) UCP2 and UCP3 interacting with the MCU complex prevented the T3-induced alterations. Analysis of mRNA expression revealed that the T3-dependent changes in mitochondrial metabolism of MCF7 cells rely on upregulation of the inositol 1,4,5-trisphosphate receptor (IP3R) isoforms IP3R1 and IP3R3. This finding was further supported by live cell imaging, as there were no T3-related differences observed in MCF7 cells in the case of siRNA-induced knockdown of IP3R1 or IP3R3, neither in [Ca2+]mito uptake nor in [ATP]mito. Furthermore, we found that MCF7 cells might use the elevated metabolic activity to promote cell proliferation. Notably, the increased cell proliferation is associated with an altered [Ca2+]mito uptake since inhibition of MCU or UCP2/3 counteracted the T3-induced proliferation boost. Based on our results, breast cancer cells utilize T3-dependent [Ca2+]mito -remodeling to boost [ATP]mito production and cell proliferation via an upregulation of different IP3R isoforms. Since the observed T3-induced effects rely on elevated [Ca2+]mito uptake, an inhibition of components involved in this process might provide a new therapeutic aspect inhibiting the proliferation of specific cancer cells.