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Published on: September 7, 2012
Influence of Tl(+) on mitochondrial permeability transition pore in Ca(2+)-loaded rat liver mitochondria
Sergey M Korotkov1, Nils-Erik L Saris
1Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg. korotkov@SK1645.spb.edu
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.
Insights
Thallium (Tl+) triggers the mitochondrial permeability transition pore (MPTP) opening in rat liver mitochondria, but only when calcium ions (Ca2+) are present. This effect is modulated by various ions and inhibitors, suggesting specific binding sites involved.
Area of Science:
- Mitochondrial physiology
- Toxicology
- Biochemistry
Background:
- The mitochondrial permeability transition pore (MPTP) plays a crucial role in cell death pathways.
- Understanding the triggers and modulators of MPTP opening is vital for comprehending mitochondrial dysfunction.
Purpose of the Study:
- To investigate the effect of thallium (Tl+) on MPTP opening in rat liver mitochondria.
- To elucidate the role of calcium ions (Ca2+) and other factors in Tl+-induced MPTP opening.
Main Methods:
- Energized rat liver mitochondria were loaded with Ca2+.
- MPTP opening was assessed by measuring mitochondrial swelling and membrane potential dissipation.
- Respiration rates (state 4, state 3, and DNP-stimulated) were measured.
- Effects of various monovalent cations, inorganic phosphate, and MPTP inhibitors were evaluated.
Main Results:
- Tl+ induced MPTP opening in Ca2+-loaded mitochondria, evidenced by swelling and membrane potential loss.
- Respiration was decreased by Tl+ exposure.
- The Tl+ effect was potentiated by inorganic phosphate and certain monovalent cations (K+ > Na+ > NH4+ ≥ Li+).
- MPTP inhibitors (ADP, CsA, Mg2+, Li+, rotenone, EGTA, ruthenium red) attenuated Tl+-induced opening.
- Maximal swelling in rotenone-free media indicated Ca2+ uptake driven by endogenous substrates.
- Tl+ stimulated MPTP opening specifically in the presence of Ca2+, unlike other heavy metals.
Conclusions:
- Tl+ acts as a potent inducer of MPTP opening, but requires the presence of Ca2+.
- The mechanism may involve Ca2+-binding sites near respiratory complex I and the adenine nucleotide translocase.
- These findings contribute to understanding Tl+ toxicity at the mitochondrial level.
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