Mitochondrial effects of triarylmethane dyes

被引:57
作者
Kowaltowski, AJ [1 ]
Turin, J
Indig, GL
Vercesi, AE
机构
[1] Univ Estadual Campinas, Dept Patol Clin, Fac Ciencias Med, Campinas, SP, Brazil
[2] Univ Wisconsin, Sch Pharm, Madison, WI 53706 USA
基金
巴西圣保罗研究基金会;
关键词
mitochondria; triarylmethane dyes; photodynamic therapy; respiration; mitochondrial permeability transition; cyclosporin A; calcium; proton transport;
D O I
10.1023/A:1005421112345
中图分类号
Q6 [生物物理学];
学科分类号
071011 ;
摘要
The mitochondrial effects of submicromolar concentrations of six triarylmethane dyes, with potential applications in antioncotic photodynamic therapy, were studied. All dyes promoted an inhibition of glutamate or succinate-supported respiration in uncoupled mitochondria, in a manner stimulated photodynamically. No inhibition of N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) supported respiration was observed, indicating that these dyes do not affect mitochondrial complex IV. When mitochondria were energized with TMPD in the absence of an uncoupler, treatment with victoria blue R, B, or BO, promoted a dissipation of mitochondrial membrane potential and increase of respiratory rates, compatible with mitochondrial uncoupling. This effect was observed even in the dark, and was not prevented by EGTA, Mg2+ or cyclosporin A, suggesting that it is promoted by a direct effect of the dye on inner mitochondrial membrane permeability to protons. Indeed, victoria blue R, B, and BO promoted swelling of valinomycin-treated mitochondria incubated in a hyposmotic K+-acetate-based medium, confirming that these dyes act as classic protonophores such as FCCP. On the other hand, ethyl violet, crystal violet, and malachite green promoted a dissipation of mitochondrial membrane potential, accompanied by mitochondrial swelling, which was prevented by EGTA, Mg2+, and cyclosporin A, demonstrating that these drugs induce mitochondrial permeability transition. This mitochondrial permeabilization was followed by respiratory inhibition, attributable to cytochrome c release, and was caused by the oxidation of NAD(P)H promoted by these drugs.
引用
收藏
页码:581 / 590
页数:10
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