Acrylic acid induces the glutathione-independent mitochondrial permeability transition in vitro.
Acrylic acid (AA) is used widely in the synthesis of esters essential in the production of paints, adhesives, plastics, and coatings. The minimal systemic toxicity of AA is attributed to its rapid oxidation to acetyl-CoA and CO2 via the vitamin B12-independent beta-oxidation pathway. This oxidation is localized to the mitochondria and preliminary evidence suggests a possible inhibition of mitochondrial metabolism by acrylic acid. The purpose of this investigation was to evaluate whether AA interferes with mitochondrial bioenergetics in vitro. Incubation of isolated rat liver mitochondrial with AA resulted in a dose-dependent induction of the mitochondrial permeability transition (MPT). This was evidenced by an increased sensitivity to calcium-induced stimulation of state 4 oxygen consumption, depolarization of membrane potential, and swelling, all of which were prevented by preincubating the mitochondrial with cyclosporine A, a potent and specific inhibitor of the mitochondrial permeability transition pore. Both N-ethylmaleimide (NEM) and dithiothreitol (DTT) showed only partial protection against induction of the MPT by AA. Associated with the induction of the MPT by AA was the loss of mitochondrial glutathione (GSH), which was due to efflux from the matrix rather than oxidation to GSSG. Cyclosporine A, by inhibiting the permeability transition, prevented the AA-induced loss of mitochondrial GSH. In conclusion, AA increases the sensitivity of isolated mitochondria in vitro to the calcium-dependent induction of the MPT. Although the molecular mechanism has yet to be defined, it does not appear to be related to the oxidation of critical thiols.
Custodio
J B
JB
Department of Biochemistry and Molecular Biology, University of Minnesota School of Medicine, Duluth 55812, USA.
Palmeira
C M
CM
Moreno
A J
AJ
Wallace
K B
KB
D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004734:Energy Metabolism; D005978:Glutathione / Q000378:metabolism*; D007425:Intracellular Membranes / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D000179:Acrylates; D005978:Glutathione; C036658:acrylic acid; D002118:Calcium