[Destabilization of the cytosolic calcium level and cardiomyocyte death in the presence of long-chain fatty acid derivatives].
It has been shown using the fluorescent microscopy technique that long-chain fatty acid derivatives, myristoylcarnitine and palmitoylcarnitine, exert the most toxic effect on rat ventricular cardiomyoctes. The addition of 20-50 microM acylcarnitines increases calcium concentration in cytoplasm ([Ca2+]i) and causes cell death after the 4-8 min lag-period. This effect is independent on extracellular calcium and L-type calcium channel inhibitors. Free acids (myristic and palmitic acids) at a concentration of 300-500 microM have a little effect on [Ca2+]i within 30 min. We suggest that the toxic effect is due to the activation of sarcoplasmic reticulum calcium channels by acylcarnitines and resulting acyl-CoA. Mitochondria play a role of calcium-buffer system in these conditions. The calcium capacity of this buffer determines the lag-period. Phosphate increases the calcium capacity of mitochondrial 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 mitochondrial 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.
Berezhnov
A V
AV
Fedotova
E I
EI
Nenov
M N
MN
Kokoz
Iu M
IuM
Zinchenko
V P
VP
Dynnik
V V
VV
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D002331:Carnitine / Q000031:analogs & derivatives* / Q000633:toxicity; D016923:Cell Death; D003600:Cytosol / Q000378:metabolism*; D066298:In Vitro Techniques; D008929:Mitochondria, Heart / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009227:Myristic Acids / Q000633:toxicity*; D010172:Palmitoylcarnitine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000502:physiology
D015220:Calcium Channels; D009227:Myristic Acids; C538774:myristoylcarnitine; D010172:Palmitoylcarnitine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002331:Carnitine; D002118:Calcium