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

Abstract

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 (50μM) 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).