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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/C1428    most recent 00006.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Azarashvili, T. Articles by Reiser, G. PubMed PubMed Citation Articles by Azarashvili, T. Articles by Reiser, G.

CELLULAR AND MITOCHONDRIAL METABOLISM

Ca²⁺-dependent permeability transition regulation in rat brain mitochondria by 2',3'-cyclic nucleotides and 2',3'-cyclic nucleotide 3'-phosphodiesterase

¹Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Magdeburg, Germany; and ²Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Pushchino, Moscow, Russia

Submitted 8 January 2009 ; accepted in final form 2 April 2009

Recent evidence indicates that 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), a marker enzyme of myelin and oligodendrocytes, is also present in neural and nonneural mitochondria. However, its role in mitochondria is still completely unclear. We found CNP in rat brain mitochondria and studied the effects of CNP substrates, 2',3'-cyclic nucleotides, on functional parameters of rat brain mitochondria. 2',3'-cAMP and 2',3'-cNADP stimulated Ca²⁺ overload-induced Ca²⁺ release from mitochondrial matrix. This Ca²⁺ release under threshold Ca²⁺ load correlated with membrane potential dissipation and mitochondrial swelling. The effects of 2',3'-cyclic nucleotides were suppressed by cyclosporin A, a potent inhibitor of permeability transition (PT). PT development is a key stage in initiation of apoptotic mitochondria-induced cell death. 2',3'-cAMP effects were observed on the functions of rat brain mitochondria only when PT was developed. This demonstrates involvement of 2',3'-cAMP in PT regulation in rat brain mitochondria. We also discovered that, under PT development, the specific enzymatic activity of CNP was reduced. Thus we hypothesize that suppression of CNP activity under threshold Ca²⁺ load leads to elevation of 2',3'-cAMP levels that, in turn, promote PT development in rat brain mitochondria. Similar effects of 2',3'-cyclic nucleotides were observed in rat liver mitochondria. Involvement of CNP in PT regulation was confirmed in experiments using mitochondria from CNP-knockdown oligodendrocytes (OLN93 cells). CNP reduction in these mitochondria correlated with lowering the threshold for Ca²⁺ overload-induced Ca²⁺ release. Thus our results reveal a new function for CNP and 2',3'-cAMP in mitochondria, being a regulator/promotor of mitochondrial PT.

oligodendrocyte mitochondria; 2',3'-cyclic nucleotide 3'-phosphodiesterase; permeability transition; calcium transport

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