National
Interakcia mitochondriálneho chloridového kanálu s translokátorovým proteínom | |
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Program: | VEGA |
Project leader: | Mgr. Ševčíková Tomášková Zuzana, PhD. |
Annotation: | Cardiac arrhythmias are one of the most common causes of death in the world. Arrhythmias also arise as a result of ischemia/reperfusion, when changes in nutrient and oxygen supply occur. Oxygen radicals may increase during reperfusion. Both metabolic and oxidative stress have been shown to result in arrhythmias due to cyclic changes in the mitochondrial membrane potential. These changes are mediated by chloride channels, which are thought to be identical to the CLIC5 isoform of intracellular chloride channels. Cardioprotective effects at the level of cells and the whole heart were observed after application of a specific ligand of mitochondrial translocator protein TSPO – 4-chlorodiazepam (4Cl-DZP), but also after application of a non-specific anion channel inhibitor. 4Cl-DZP is thought to act on chloride channel activity indirectly, via the TSPO protein, but no details of this interaction are known. The aim of our project is to describe the relationship between CLIC5 chloride channels and the TSPO receptor. |
Duration: | 1.1.2023 – 31.12.2026 |
mClicID – Na stope identity mitochondriálneho chloridového kanálu | |
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Program: | APVV |
Project leader: | Mgr. Ševčíková Tomášková Zuzana, PhD. |
Annotation: | Mitochondrial chloride channels are involved in the regulation of the mitochondrial membrane potential Ψm. In in vitro conditions, it was observed that oxidative stress results in oscillations of Ψm, which leads to the shortening of the action potential on the plasma membrane of cardiomyocytes and the occurrence of arrhythmias, mediated by the production of ATP in the mitochondria. At the level of the whole heart, arrhythmias were observed as a consequence of ischemia-reperfusion. Specific ligands of the translocator protein (TSPO) prevent the occurrence of post-ischemic arrhythmias. The use of a non-specific chloride channel blocker led to the same effect. TSPO ligands inhibit the mitochondrial chloride channels at nanomolar concentrations, suggesting that the TSPO protein mediates channel block. Thus, TSPO is likely to be in close contact with the chloride channel. Mitochondrial chloride channels are well described at the electrophysiological level, but their molecular identity remains unclear. Recently, two isoforms of chloride intracellular channels (CLICs) have been shown to be localized in mitochondria. However, CLIC channels have only been described in an artificial system – overexpressed in host cells. Mitochondrial chloride channels from native membranes are assumed to be identical to one of the two mitochondrial CLIC isoform. The aim of the presented project is to verify the hypothesis that the measured native chloride channels from cardiac mitochondria are members of the CLIC family and whether the given CLIC isoform and TSPO are in close physical contact. We assume that the obtained results will help clarify the molecular identity of the mitochondrial chloride channel, which represents a significant potential target for preventing the occurrence of post-ischemic arrhythmias. |
Duration: | 1.7.2023 – 30.6.2027 |