Species-specific modulation of the mitochondrial permeability transition by norbormide

Biochimica Et Biophysica Acta
Fernanda RicchelliSergio Bova

Abstract

In the present study, we show that norbormide stimulates the opening of the permeability transition pore (PTP) in mitochondria from various organs of the rat but not of guinea pig and mouse. Norbormide does not affect the basic parameters that modulate the PTP activity since the proton electrochemical gradient, respiration, phosphorylation and Ca(2+) influx processes are only partially affected. On the other hand, norbormide induces rat-specific changes in the fluidity of the lipid interior of mitochondrial membranes, as revealed by fluorescence anisotropy of various reporter molecules. Such changes increase the PTP open probability through the internal Me(2+) regulatory site. The lack of PTP opening by norbormide is matched by a negligible perturbation of internal lipid domains in guinea pig and mouse, suggesting that the drug does not gain access to the matrix in the mitochondria from these species. Consistent with this interpretation, we demonstrate a preferential interaction of norbormide with the mitochondrial surface leading to alterations of the Me(2+) binding affinity for the external PTP regulatory site. Our findings indicate that norbormide affects Me(2+) binding to the regulatory sites of the PTP, and suggest that th...Continue Reading

References

Jul 1, 1966·Journal of Medicinal Chemistry·G I PoosA P Roszkowski
Aug 11, 1982·Biochimica Et Biophysica Acta·J Slavík
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Apr 24, 1964·Science·A P ROSZKOWSKIR J MOHRBACHER

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Citations

Jul 1, 2009·Environmental Toxicology and Pharmacology·Shanthinie RavindranMalcolm Tingle
Jan 1, 2009·Environmental Toxicology and Pharmacology·Shanthinie RavindranMalcolm Tingle
Sep 25, 2014·The Journal of Membrane Biology·Jia-Ling GaoJie Dai
Aug 26, 2015·The Journal of Membrane Biology·Jia-Ling GaoJie Dai
May 19, 2007·Biochimica Et Biophysica Acta·Alessandra ZulianFernanda Ricchelli
Oct 11, 2016·Frontiers in Pharmacology·Claudio D'AmoreSergio Bova

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