Influence of Tl+ on mitochondrial permeability transition pore in Ca2+-loaded rat liver mitochondria

Abstract

The Tl(+)-induced opening of the MPTP in Ca(2+)-loaded rat liver mitochondria energized by respiration on the substrates succinate or glutamate plus malate was recorded as increased swelling and dissipation of mitochondrial membrane potential as well as decreased state 4, or state 3, or 2,4-dinitrophenol-stimulated respiration. These effects of Tl(+) increased in nitrate media containing monovalent cations in the order of Li(+) < NH (4) (+) ≤ Na(+) < K(+). They were potentiated by inorganic phosphate and diminished by the MPTP inhibitors (ADP, CsA, Mg(2+), Li(+), rotenone, EGTA, and ruthenium red) both individually and more potently in their combinations. Maximal swelling of both non-energized and energized Ca(2+)-loaded mitochondria in rotenone-free media is an indication of Ca(2+) uptake driven by respiration on mitochondrial endogenous substrates. It is suggested that Tl(+) (distinct from Cd(2+), Hg(2+), and other heavy metals and regardless of the used respiratory substrates) can stimulate opening of the MPTP only in the presence of Ca(2+). We discuss the possible participation of Ca(2+)-binding sites, located near the respiratory complex I and the adenine nucleotide translocase, in inducing opening of the MPTP.

Y 3+ , La 3+ , and some bivalent metals inhibited the opening of the Tl + -induced permeability transition pore in Ca 2+ -loaded rat liver mitochondria

“…La 3+ , RR and EGTA inhibited the increase in IMM permeability for acetyl-CoA in Ca 2+ loaded RLM [39]. We showed that the MPTP opening was markedly diminished in the presence of the MPTP inhibitors (ADP, CsA, Mg 2+ , and Li + ) [3]. With this as our background, our aim was to study the influence of bivalent metal ions (Sr 2+ , Ba 2+ , Mn 2+ , Co 2+ , and Ni 2+ ) as well as Y 3+ and La 3+ on the Tl + -induced MPTP opening in the inner membrane of CaRLM.…”

“…Wistar adult male rats (200-250 g) were used for liver mitochondria isolation according to the standard procedure [3]. Mitochondria were suspended in a buffer containing 250 mM sucrose, 3 mM Tris-HCl (pH 7.3), and 0.5 mM EGTA.…”

“…We observed earlier that the calcium load of rat liver mitochondria (RLM) favored the opening of the Tl + -induced mitochondrial permeability transition pore (MPTP) in their IMM [3]. This opening was accompanied by both increased swelling or ΔΨ mito dissipation, and decreased state 4, state 3 and 2,4-dinitrophenol (DNP)-uncoupled respiration of the mitochondria [3]. Our previous studies showed that Sr 2+ , Mn 2+ , and ruthenium red (RR) but not Ba 2+ inhibited deleterious effects of Cd 2+ on mitochondrial respiration [4] and decreased Cd 2+ -induced MPTP opening in the inner membrane [5] of the RLM.…”

“…Considerable structural damages in mitochondrial membranes were found in experiments with Tl-poisoned rats ( [1] and references herein). Toxicity of Tl + is related to its ability to easily penetrate the inner mitochondrial membrane (IMM) and to release Ca 2+ from intracellular compartments ( [1][2][3] and references inside). We observed earlier that the calcium load of rat liver mitochondria (RLM) favored the opening of the Tl + -induced mitochondrial permeability transition pore (MPTP) in their IMM [3].…”

“…Toxicity of Tl + is related to its ability to easily penetrate the inner mitochondrial membrane (IMM) and to release Ca 2+ from intracellular compartments ( [1][2][3] and references inside). We observed earlier that the calcium load of rat liver mitochondria (RLM) favored the opening of the Tl + -induced mitochondrial permeability transition pore (MPTP) in their IMM [3]. This opening was accompanied by both increased swelling or ΔΨ mito dissipation, and decreased state 4, state 3 and 2,4-dinitrophenol (DNP)-uncoupled respiration of the mitochondria [3].…”