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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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Abstract

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.

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Abbreviations

ACR:

Acceptor control ratio

CsA:

Cyclosporin A

MCU:

Mitochondrial calcium uniporter

MPT:

Mitochondrial permeability transition

ROS:

Reactive oxygen species

Ru red:

Ruthenium red

FCCP:

Carbonyl cyanide p-trifluoro-methoxyphenyl hydrazine

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Authors and Affiliations

  1. Department of Biophysics, University of Bialystok, Ciolkowskiego 1J, 15-245, Bialystok, Poland

    Szymon Sekowski & Maria Zamaraeva

  2. National University of Uzbekistan named after Mirzo Ulugbek, Vuzgorodok, 700174, Tashkent, Uzbekistan

    Oksana Charishnikova

  3. Department of Biochemistry, Yanka Kupala State University of Grodno, Blvd. Len. Kom. - 50, 230030, Grodno, Belarus

    Tatsiana Ilyich, Lyudmila Kiryukhina, Elena Lapshina & Ilya Zavodnik

  4. Department of Biotechnology, Polessky State University, Dnieprovskoy Flotilii, 23, 225710, Pinsk, Brest Region, Belarus

    Vitali Cheshchevik & Nina Cheshchevik

  5. Department of Pathophysiology, State Medical University of Grodno, Gorkogo, 80, 230015, Grodno, Belarus

    Iosif Dremza

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  1. Tatsiana Ilyich
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  2. Oksana Charishnikova
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  3. Szymon Sekowski
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  4. Maria Zamaraeva
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  9. Elena Lapshina
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  10. Ilya Zavodnik
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Correspondence to Ilya Zavodnik.

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Ilyich, T., Charishnikova, O., Sekowski, S. et al. Ferutinin Induces Membrane Depolarization, Permeability Transition Pore Formation, and Respiration Uncoupling in Isolated Rat Liver Mitochondria by Stimulation of Ca2+-Permeability. J Membrane Biol 251, 563–572 (2018). https://doi.org/10.1007/s00232-018-0032-0

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