Inorganic phosphate stimulates the toxic effects of Tl⁺ in rat liver mitochondria

Abstract

We studied action of inorganic phosphate (P(i)) on toxic effects of Tl+ in isolated rat liver mitochondria. This is a convenient model to study the toxicity of heavy metals. P(i) markedly retarded contraction of energized mitochondria swollen in the TlNO3 medium and even stronger stimulated swelling and state 4 of succinate-energized mitochondria in the TlNO3 medium. A valinomycin-induced decrease of K+-diffusion potential was also accelerated by Tl+ in the presence of P(i). The mitochondrial permeability transition pore in the medium containing Ca2+, TlNO3, and nitrates of univalent cations was distinctly stimulated by P(i). However, P(i) did not affect both the Tl+-stimulated swelling of nonenergized mitochondria in the TlNO3 medium and swelling of energized mitochondria in the Tl acetate medium. Respiration stimulated by 2,4-dinitrophenol and monoamine oxidase activity of energized mitochondria were not affected by Tl+ regardless of the presence of P(i). We suggested that stimulation by P(i) of toxic action of Tl+ in mitochondria and cells could be due to even greater enhancement of uncoupling of mitochondria as shown by an additional increase of swelling and state 4, and in the greater probability of opening of MPTP in the presence of P(i) and Ca2+.

Tl+ Showed Negligible Interaction with Inner Membrane Sulfhydryl Groups of Rat Liver Mitochondria, but Formed Complexes with Matrix Proteins

“…These findings can be explained by the fact that DTT reduces Cd 2+ inhibition of respiratory enzymes that are not affected by Tl + . Conversely, we postulated earlier that a more potent decrease in state 4, state 3, and DNP‐stimulated respiration of RLM in nitrate salt media containing TlNO 3 and Ca 2+ was due to massive mitochondrial swelling (Figures and ). The effects of cations on respiration and swelling of energized RLM in nitrate media increased in the order of Ca 2+ < Tl + + Ca 2+ < Cd 2+ < Cd 2+ + Ca 2+ .…”

“…We have earlier suggested that the interaction of Tl + with MSG may be one of the causes of thallium toxicity . The interaction would decrease the content of IMM SH groups, similar to the effects of PhAsO or Ag + . Conversely, we found an increase in IMM content in experiments with RLM, incubated and frozen in media containing TlNO 3 (Figures and , panels A–D).…”

“…Cd 2+ inhibited respiratory enzymes, resulting in a decrease in state 4, state 3, and DNP-stimulated respiration [12,14,15]. Nevertheless, Tl + alone or Cd 2+ after injected DTT stimulated swelling, state 4, and contraction of energized mitochondria, swollen in salt media [11,13,19,33,37]. Retarded Cd 2+ inhibition of state 3 or DNP-stimulated respiration occurred as well.…”

“…We presumed that the reaction of Tl + with SH groups of cellular and mitochondrial proteins could be one of the causes of thallium toxicity, in analogy with the effects of the above-mentioned heavy metals [32][33][34][35][36]. Accordingly, Tl + -induced glutathione depletion and the ROS-accelerated production are probably accompanied by a reaction of Tl + with the MSG [34,[36][37][38]. However, the low affinity of Tl + to molecular SH groups [7,33,35,39] is in agreement with the finding that Tl + does not inhibit respiratory enzymes [33,35,39] nor mitochondrial respiration [19,33,35,37,40,41].…”

“…Accordingly, Tl + -induced glutathione depletion and the ROS-accelerated production are probably accompanied by a reaction of Tl + with the MSG [34,[36][37][38]. However, the low affinity of Tl + to molecular SH groups [7,33,35,39] is in agreement with the finding that Tl + does not inhibit respiratory enzymes [33,35,39] nor mitochondrial respiration [19,33,35,37,40,41]. However, we demonstrated increased ion permeability [40] and MPTP opening [41] in the IMM of rat liver mitochondria (RLM) in medium containing TlNO 3 and nitrate salts.…”