Ferutinin Induces Membrane Depolarization, Permeability Transition Pore Formation, and Respiration Uncoupling in Isolated Rat Liver Mitochondria by Stimulation of Ca2+-Permeability
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It is well known that the terpenoid ferutinin (4-oxy-6-(4-oxybenzoyloxy) dauc-8,9-en), isolated from the plant Ferula tenuisecta, considerably increases the permeability of artificial and cellular membranes to Ca2+-ions and produces apoptotic cell death in different cell lines in a mitochondria-dependent manner. The present study was designed for further evaluation of the mechanism(s) of mitochondrial effects of ferutinin using isolated rat liver mitochondria. Our findings provide evidence for ferutinin at concentrations of 5–27 µM to decrease state 3 respiration and the acceptor control ratio in the case of glutamate/malate as substrates. Ferutinin alone (10–60 µM) also dose-dependently dissipated membrane potential. In the presence of Ca2+-ions, ferutinin (10–60 µM) induced considerable depolarization of the inner mitochondrial membrane, which was partially inhibited by EGTA, and permeability transition pore formation, which was diminished partly by cyclosporin A, and did not influence markedly the effect of Ca2+ on mitochondrial respiration. Ruthenium Red, a specific inhibitor of mitochondrial calcium uniporter, completely inhibited Ca2+-induced mitochondria swelling and membrane depolarization, but did not affect markedly the stimulation of these Ca2+-dependent processes by ferutinin. We concluded that the mitochondrial effects of ferutinin might be primarily induced by stimulation of mitochondrial membrane Ca2+-permeability, but other mechanisms, such as driving of univalent cations, might be involved.
KeywordsFerutinin Mitochondria Ca2+-ionophores Membrane potential Respiration Permeability transition pore
Acceptor control ratio
Mitochondrial calcium uniporter
Mitochondrial permeability transition
Reactive oxygen species
- Ru red
Carbonyl cyanide p-trifluoro-methoxyphenyl hydrazine
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
The informed consent was obtained from all the individual participants involved in the study.
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