RGD Reference Report - Ca2+-dependent permeability transition regulation in rat brain mitochondria by 2',3'-cyclic nucleotides and 2',3'-cyclic nucleotide 3'-phosphodiesterase. - Rat Genome Database

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

Authors: Azarashvili, T  Krestinina, O  Galvita, A  Grachev, D  Baburina, Y  Stricker, R  Evtodienko, Y  Reiser, G 
Citation: Azarashvili T, etal., Am J Physiol Cell Physiol. 2009 Jun;296(6):C1428-39. Epub 2009 Apr 8.
RGD ID: 6480491
Pubmed: PMID:19357238   (View Abstract at PubMed)
DOI: DOI:10.1152/ajpcell.00006.2009   (Journal Full-text)

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 Ca(2+) overload-induced Ca(2+) release from mitochondrial matrix. This Ca(2+) release under threshold Ca(2+) 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 Ca(2+) 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 Ca(2+) overload-induced Ca(2+) release. Thus our results reveal a new function for CNP and 2',3'-cAMP in mitochondria, being a regulator/promotor of mitochondrial PT.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
regulation of mitochondrial membrane permeability  IMP 6480491 RGD 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
mitochondrial inner membrane  IDA 6480491 RGD 
mitochondrial outer membrane  IDA 6480491 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
2',3'-cyclic-nucleotide 3'-phosphodiesterase activity  IDA 6480491 RGD 
cyclic nucleotide binding  IDA 64804912' more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cnp  (2',3'-cyclic nucleotide 3' phosphodiesterase)


Additional Information