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

Abstract

The Tl⁺-induced opening of the MPTP in Ca²⁺-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, Mg²⁺, Li⁺, rotenone, EGTA, and ruthenium red) both individually and more potently in their combinations. Maximal swelling of both non-energized and energized Ca²⁺-loaded mitochondria in rotenone-free media is an indication of Ca²⁺ uptake driven by respiration on mitochondrial endogenous substrates. It is suggested that Tl⁺ (distinct from Cd²⁺, Hg²⁺, and other heavy metals and regardless of the used respiratory substrates) can stimulate opening of the MPTP only in the presence of Ca²⁺. We discuss the possible participation of Ca²⁺-binding sites, located near the respiratory complex I and the adenine nucleotide translocase, in inducing opening of the MPTP.