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2 Acta Biochimica Polonica

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Mitochondrial respiratory chain inhibitors modulate the metal-induced inner mitochondrial membrane permeabilization

100%

Belyaeva E. A.

Acta Biochimica Polonica

2010

tom 57

nr 4

435-441

To elucidate the molecular mechanisms of the protective action of stigmatellin (an inhibitor of complex III of mitochondrial electron transport chain, mtETC) against the heavy metal-induced cytotoxicity, we tested its effectiveness against mitochondrial membrane permeabilization produced by heavy metal ions Cd2+, Hg2+, Cu2+ and Zn2+, as well as by Ca2+ (in the presence of Pi) or Se (in form of Na2SeO3) using isolated rat liver mitochondria. It was shown that stigmatellin modulated mitochondrial swelling produced by these metals/metalloids in the isotonic sucrose medium in the presence of ascorbate plus tetramethyl-p-phenylenediamine (complex IV substrates added for energization of the mitochondria). It was found that stigmatellin and other mtETC inhibitors enhanced the mitochondrial swelling induced by selenite. However, in the same medium, all the mtETC inhibitors tested as well as cyclosporin A and bongkrekic acid did not significantly affect Cu2+-induced swelling. In contrast, the high-amplitude swelling produced by Cd2+, Hg2+, Zn2+, or Ca2+ plus Pi was significantly depressed by these inhibitors. Significant differences in the action of these metals/metalloids on the redox status of pyridine nucleotides, transmembrane potential and mitochondrial respiration were also observed. In the light of these results as well as the data from the recent literature, our hypothesis on a possible involvement of the respiratory supercomplex, formed by complex I (P-site) and complex III (S-site) in the mitochondrial permeabilization mediated by the mitochondrial transition pore, is updated.

Cd2+-promoted mitochondrial permeability transition: a comparison with other heavy metals.

51%

Belyaeva E. A. , Glazunov V. V. , Korotkov S. M.

Acta Biochimica Polonica

2004

tom 51

nr 2

545-551

We compared action of Cd2+, Hg2+, and Cu2+ on isolated rat liver mitochondria in the absence of added Ca2+ and Pi. The heavy-metal ions produced dose-dependently: (1) enhanced membrane permeabilizaton manifested in mitochondrial swelling and activation of basal respiration, (2) inhibition of uncoupler-stimulated respiration, and (3) membrane potential dissipation. Among the metals, Cu2+ exhibited maximal stimulatory effect on basal respiration and minimal inhibitory action on DNP-uncoupled respiration whilst Cd2+ promoted the strongest depression of uncoupled respiration and the largest swelling in NH4NO3 medium. Dithiothreitol induced a basal respiration release if added after high [Cd2+] and [Hg2+], and the stimulation was CsA-insensitive.