The opening of the mitochondrial permeability transition (MPT) pore in its low conductance state occurs in the hepatocytes of the Baltic lamprey (Lampetra fluviatilis L.) during reversible metabolic depression during the pre-spawning migration period when exogenous feeding is turned off, as we previously discovered. The depression appears in the lamprey’s final year of life and is caused by reversible mitochondrial malfunction (mitochondrial uncoupling in winter and the coupling in spring). The goal of this work was to better understand the mechanism(s) of MPT pore induction in the lamprey liver, and the pore inducers employed were Ca2+ plus Pi (and/or laurate) and Cd2+. In isotonic sucrose and ammonium nitrate solution, Ca2+ with Pi generated high-amplitude swelling of the isolated “winter” mitochondria, whereas low and high Cd2+ did not cause mitochondrial swelling in these assay media. Low Cd2+ increased the suppression of the “winter” mitochondria’s basal respiration rate fueled by NAD-dependent substrates, but the same concentrations of the heavy metal elicited partial activation on FAD-dependent substrates. The above-mentioned alterations in the “winter” mitochondria caused by Cd2+ or Ca2+ with Pi were only slightly sensitive to cyclosporine A, CsA (a powerful pharmacological desensitizer of the MPT pore) alone, and they were not susceptible to dithiothreitol (a dithiol reducing agent, DTT). By measuring the trans-membrane potential of the “spring” lamprey liver mitochondria, we discovered that Cd2+ caused a decrease in membrane potential on both types of respiratory substrates under test, which was significantly slowed by CsA; additionally, DTT partially restored the membrane potential. The effects of various membrane permeability and electron transport chain (mitoETC) modulators, such as heparin, nupercaine, laurate, BSA, CsA, DTT, and heavy metals, on the lamprey liver mitochondria function are discussed, as well as the reversible season-dependent disturbance of mitoETC complex I (CI) activity (including reverse electron transport), which suggests that A/D conversion of CI in the MPT pore for reverse electron transport.
Elena A. Belyaeva
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez pr. 44, 194223, St.-Petersburg, Russia.
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