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1 Department of Physiology & Pathophysiology, University of Witten/Herdecke, Witten, Nordrhein Westfalen, Germany; School of Biological Sciences, University of Manchester, Manchester, Lancashire, United Kingdom
2 Department of Physiology & Pathophysiology, University of Witten/Herdecke, Witten, Nordrhein Westfalen, Germany
* To whom correspondence should be addressed. E-mail: frank.thevenod{at}uni-wh.de.
Cd2+ induces apoptosis of kidney proximal tubule (PT) cells. Mitochondria play a pivotal role in toxic compound-induced apoptosis by releasing cytochrome c. Our objective was to investigate the mechanisms underlying Cd2+-induced cytochrome c release from mitochondria in rat PT cells. Using Hoechst 33342 or MTT assay, 10 µM Cd2+ induced ~5-10% apoptosis in PT cells at 6 and 24 hours, which was associated with cytochrome c and apoptosis inducing factor release at 24 hours only. This correlated with previously described maximal intracellular Cd2+ concentrations at 24 hours, suggesting that elevated Cd2+ may directly induce mitochondrial liberation of pro-apoptotic factors. Indeed, Cd2+ caused swelling of energized isolated kidney cortex mitochondria (EC50 ~ 9 µM) and cytochrome c release, which were independent of permeability transition pore (PTP) opening since PTP inhibitors cyclosporin A or bongkrekic acid had no effect. On the contrary, Cd2+ inhibited swelling and cytochrome c release induced by PTP openers (PO43- or H2O2 + Ca2+). The mitochondrial Ca2+ uniporter (MCU) played a key role in mitochondrial damage: 1) MCU inhibitors (La3+, ruthenium red, Ru360) prevented swelling and cytochrome c release; 2) ruthenium red attenuated Cd2+ inhibition of PO43--induced swelling. Using the Cd2+-sensitive fluorescent indicator FluoZin-1, Cd2+ was also taken up by mitoplasts. The aquaporin inhibitor, AgNO3, abolished Cd2+-induced swelling of mitoplasts. This could be partially mediated by activation of the mitoplast-enriched water channel aquaporin 8. Thus cytosolic Cd2+ concentrations exceeding a certain threshold may directly cause mitochondrial damage and apoptosis development by interacting with MCU and water channels in the inner mitochondrial membrane.
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