Y3 +, La3 +, and some bivalent metals inhibited the opening of the Tl+-induced permeability transition pore in Ca2 +-loaded rat liver mitochondria

We showed earlier that diminution of 2,4-dinitrophenol (DNP)-stimulated respiration and increase of both mitochondrial swelling and electrochemical potential (ΔΨmito) dissipation in medium containing TlNO3 and KNO3 were caused by opening of Tl+-induced mitochondrial permeability transition pore (MPTP) in the inner membrane of Ca2 +-loaded rat liver mitochondria. The MPTP opening was studied in the presence of bivalent metal ions (Sr2 +, Ba2 +, Mn2 +, Co2 + and Ni2 +), trivalent metal ions (Y3 + and La3 +), and ruthenium red. We found that these metal ions (except Ba2 + and Co2 +) as well as ruthenium red inhibited to the MPTP opening that manifested in preventing both diminution of the DNP-stimulated respiration and increase of the swelling and of the ΔΨmito dissipation in medium containing TlNO3, KNO3, and Ca2 +. Inhibition of the MPTP opening by Sr2 + and Mn2 + is suggested because of their interaction with high affinity Ca2 + sites, facing the matrix side and participating in the MPTP opening. The inhibitory effects of metal ions (Y3 +, La3 +, and Ni2 +), and ruthenium red are accordingly discussed in regard to competitive and noncompetitive inhibition of the mitochondrial Ca2 +-uniporter. High concentrations (50 μM) of Y3 + and La3 + favored of MPTP opening in the inner membrane of rat liver mitochondria in Ca2 + free medium containing TlNO3. The latter MPTP opening was markedly eliminated by MPTP inhibitors (cyclosporine A and ADP).

Sr2 + and Mn2 + decreased opening of the Tl+-induced mitochondrial permeability transition pore (MPTP). Y3 +, La3 +, Ni2 +, and RR inhibit transport of Ca2 + into mitochondria in medium with TlNO3. High Y3 + and La3 + induced MPTP in medium with TlNO3. Ca2 +/H+ exchanger supported Ca2 + efflux from the matrix in medium with TlNO3.Figure optionsDownload as PowerPoint slide