Mitochondria a key role in microcystin-LR kidney intoxication.
Microcystins (MCs) are a group of closely related cyclic heptapeptides produced by a variety of common cyanobacteria. These toxins have been implicated in both human and livestock mortality. Microcystin-LR could affect renal physiology by altering vascular, glomerular and urinary parameters, indicating that MC-LR could act directly on the kidney. The aim of the current work was to examine the effect of MC-LR on mitochondrial oxidative phosphorylation of rat kidney isolated mitochondria.Furthermore, microcystin-LR decreased both state 3 and carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled respiration. The transmembrane potential was strongly depressed by MC-LR in a concentration dependent manner, pointing to an uncoupling effect; however, microcystin-LR did not increase the permeability of the inner mitochondria membrane to protons. Therefore, the transmembrane decrease was a consequence of a strong inhibitory effect on redox complexes. The addition of uncoupling concentrations of MC-LR to Ca(2+)-loaded mitochondria treated with ruthenium red resulted in mitochondrial permeability transition pore (MPTP) opening, as evidenced by mitochondrial swelling in isosmotic sucrose medium. Mitochondrial swelling in the presence of Ca(2+) was prevented by cyclosporin A and was drastically inhibited by catalase and dithiothreitol, indicating the participation of mitochondrial generated reactive oxygen species in this process. From this study it can be concluded that the bioenergetic lesion promoted by microcystin-LR seems to be sufficient to explain renal injury.
La-Salete
R
R
Chemistry Department, CECAV, University of Trás-os-Montes and Alto Douro, 5001-801 Vila Real, Portugal.
Oliveira
M M
MM
Palmeira
C A
CA
Almeida
J
J
Peixoto
F P
FP
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D003576:Electron Transport Complex IV / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008387:Marine Toxins; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D052998:Microcystins / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013384:Succinate Cytochrome c Oxidoreductase / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism
D008387:Marine Toxins; D052998:Microcystins; D013384:Succinate Cytochrome c Oxidoreductase; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; C057862:cyanoginosin LR