Yessotoxin, a shellfish biotoxin, is a potent inducer of the permeability transition in isolated mitochondria and intact cells.
The diarrhetic poisoning by bivalve molluscs, diarrhetic shellfish poisoning, is due to consumption of mussels containing biotoxins produced by some Dinoflagellate species. Toxic effects of yessotoxin (YTX) include morphological alterations of mitochondria from heart and liver but the biochemical basis for these alterations is completely unknown. This paper demonstrates that YTX is a very powerful compound that opens the permeability transition pore (PTP) of the inner mitochondrial membrane of rat liver mitochondria at nanomolar concentrations. The effect requires the presence of a permissive level of calcium, by itself incapable of opening the pore. The direct effect of YTX on PTP is further confirmed by the inhibition exerted by cyclosporin A (CsA) that is known as a powerful inhibitor of PTP opening. Moreover, YTX induces membrane depolarization as shown by the quenching of tetramethylrhodamine methyl ester (TMRM), also prevented by the addition of CsA. YTX caused PTP opening in Morris Hepatoma 1C1 cells, as shown by the occurrence of CsA-sensitive depolarization within minutes of the addition of submicromolar concentrations of the toxin. These results provide a biochemical basis for the mitochondrial alterations observed in the course of intoxication with YTX, offering the first clue into the pathogenesis of diseases caused by YTX, and providing a novel tool to study the PTP in situ.
Bianchi
Cristina
C
Department of Biochemistry "G. Moruzzi", University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.
Fato
Romana
R
Angelin
Alessia
A
Trombetti
Fabiana
F
Ventrella
Vittoria
V
Borgatti
Anna Rosa
AR
Fattorusso
Ernesto
E
Ciminiello
Patrizia
P
Bernardi
Paolo
P
Lenaz
Giorgio
G
Parenti Castelli
Giovanna
G
D000818:Animals; D049872:Bivalvia / Q000737:chemistry*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D005456:Fluorescent Dyes / Q000378:metabolism; D007425:Intracellular Membranes; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D008978:Mollusk Venoms / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D035964:Oxocins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D010101:Oxygen Consumption / Q000187:drug effects; D010539:Permeability / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012235:Rhodamines / Q000378:metabolism; D013997:Time Factors
D004791:Enzyme Inhibitors; D004988:Ethers, Cyclic; D005456:Fluorescent Dyes; D008978:Mollusk Venoms; D035964:Oxocins; D012235:Rhodamines; C401833:tetramethylrhodamine methyl ester; D016572:Cyclosporine; C066632:yessotoxin; D002118:Calcium