Acetylsalicylate (ASA)-induced mitochondrial dysfunction and its potentiation by Ca2+.
Although it has been suggested that acetylsalicylate (ASA)-induced mitochondrial dysfunction plays an important role in the pathogenesis of Reye's syndrome, administration of ASA alone does not cause this syndrome in therapeutic doses. We noted, however, that Ca2+ plays important roles in the regulation of cellular functions. ASA at concentrations of 250 microM or less, which had little effect on succinate-linked respiration, impaired Ca2+ accumulation in liver mitochondria by causing an increase in Ca2+ release. ASA plus Ca2+, which in concentrations of 150 microM or less alone had little effect on mitochondrial respiration, inhibited state 3 respiration and dinitrophenol-induced uncoupling of respiration. In addition, ASA plus Ca2+ increased state 4 respiration and ATPase activity. These results indicate that ASA plus Ca2+ impaired mitochondrial ATP synthesis, and suggest that ASA and ASA-induced Ca2+ increases in cytosol form a vicious circle of effects. Furthermore, oral administration of ASA (150 mg/kg for 5 days running) to rats did not affect mitochondrial structure or liver function, but resulted in aberrations of mitochondrial respiration. These results suggest that even therapeutic doses of ASA may induce alteration in mitochondrial function.
Tomoda
T
T
Department of Pediatrics, Kochi Medical School, Japan.
Takeda
K
K
Kurashige
T
T
Enzan
H
H
Miyahara
M
M
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001241:Aspirin / Q000633:toxicity*; D002118:Calcium / Q000502:physiology*; D004357:Drug Synergism; D066298:In Vitro Techniques; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects*; D008933:Mitochondrial Swelling / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000251:Adenosine Triphosphatases; D001241:Aspirin; D002118:Calcium