Destabilization of the cytosolic calcium level and the death of cardiomyocytes in the presence of derivatives of long-chain fatty acids |
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Authors: | A. V. Berezhnov E. I. Fedotova M. N. Nenov Yu. M. Kokoz V. P. Zinchenko V. V. Dynnik |
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Affiliation: | (1) Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, 142290, Russia;(2) Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, 142290, Russia |
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Abstract: | By means of fluorescent microscopy, long-chain fatty acid derivatives, myristoylcarnitine and palmitoylcarnitine, were shown to exert the most toxic effect on rat ventricular cardiomyocytes. The addition of 20–50 μM acylcarnitines increased calcium concentration in cytoplasm ([Ca2+]i) and caused cell death after a lag-period of 4–8 min. This effect was independent of extracellular calcium level and Ca2+ inhibitors of L-type channels. Free myristic and palmitic acids at concentrations of 300–500 μM had little effect on [Ca2+]i within 30 min. We suggest that the toxic effect is due to the activation of calcium channels of sarcoplasmic reticulum by acylcarnitines and/or arising acyl-CoA. Mitochondria play a role of calcium-buffer system under these conditions. The calcium capacity of the buffer determines the duration of the lag-period. Phosphate increases the calcium capacity of mitochondria and the lag-period. In the presence of rotenone and oligomycin, the elevation of [Ca2+]i after the addition of acylcarnitines occurs without the lag-period. The exhaustion of the mitochondrial calcium-buffer capacity or significant depolarization of mitochondria leads to a rapid release of calcium from mitochondria and cell death. Thus, the activation of reticular calcium channels is the main reason of the toxicity of myristoylcarnitine and palmitoylcarnitine. |
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Keywords: | cardiomyocytes [Ca2+]i fatty acids myristoylcarnitine palmitoylcarnitine ryanodine receptor mitochondria mitochondrial [Ca2+]i-capacity |
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