Spermine Selectively Inhibits High-Conductance but not Low-Conductance Mode of the Mitochondrial Permeability Transition Pore (MPTP)

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Spermine is a biological organic polymer that has four primary amino groups. It is involved in the regulation of transcription, cell signalling and enzymatic activity. It has also been demonstrated that polyamines inhibit calcium-induced high amplitude mitochondrial swelling, suggesting their involvement in regulation of the mitochondrial Permeability Transition Pore (mPTP). Here we further investigated the mechanisms of polyamine inhibition of calcium-induced, cyclosporine A (CSA) sensitive mPTP.Experiments were performed using isolated rat liver mitochondria resuspended in sucrose based recording solution. mPTP was induced by the addition of calcium to energized mitochondria. mPTP activation was measured by three independent approaches: 1) calcium release from the mitochondria detected with calcium green; 2) mitochondrial membrane depolarization using TMRM probe and 3) mitochondrial swelling measured as a decrease of light absorbance. In control experiments, in the presence of the specific inhibitor CSA, mPTP inhibition was observed by all three approaches. However, in the presence of spermine (0.02 mM to 0.2 mM) only mitochondrial swelling was inhibited, while membrane depolarization and calcium release were not affected.These results suggest that spermine inhibited high-conductance mode of mPTP, which opening is required for induction of mitochondrial swelling in sucrose based media. However spermine did not inhibit low-conductance mode mPTP. Our data are consistent with possible distinct regulation and/or nature of the different modes of mPTP.