Ca2+-dependent permeability transition regulation in rat brain mitochondria by 2′,3′-cyclic nucleotides and 2′,3′-cyclic nucleotide 3′-phosphodiesterase
Ca2+-dependent permeability transition regulation in rat brain mitochondria by 2′,3′-cyclic nucleotides and 2′,3′-cyclic nucleotide 3′-phosphodiesterase
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DOI：
10.1152/ajpcell.00006.2009
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发表时间：
2009-06-01
影响因子：
5.5
通讯作者：
Reiser, Georg
中科院分区：
文献类型：
--
作者：
Azarashvili, Tamara;Krestinina, Olga;Reiser, Georg
[10]李文辉，李文辉. 2 '，3'-环核苷酸和2 '，3'-环核苷酸3 '-磷酸二酯酶对大鼠脑线粒体Ca ~（2+）依赖性通透性转换的调节美国生理学杂志细胞生理学296：C1428-C1439，2009年。首次发表于2009年4月8日; doi：10.1152/ajpcell.00006.2009。最近的证据表明，2 '，3'-环核苷酸3 '-磷酸二酯酶（CNP），髓鞘和少突胶质细胞的标志酶，也存在于神经和非神经线粒体。然而，它在线粒体中的作用仍然完全不清楚。我们在大鼠脑线粒体中发现了CNP，并研究了CNP底物2 '，3'-环核苷酸对大鼠脑线粒体功能参数的影响。2 '，3'-cAMP和2 '，3'-cNADP刺激Ca ~（2+）超负荷诱导的线粒体基质Ca ~（2+）释放。这种阈值Ca 2+负荷下的Ca 2+释放与膜电位耗散和线粒体肿胀相关。2 '，3'-环核苷酸的作用被一种有效的通透性转换（PT）抑制剂环孢菌素A所抑制。PT发展是凋亡性细胞凋亡诱导的细胞死亡开始的关键阶段。2 '，3'-cAMP对大鼠脑线粒体功能的影响仅见于PT时。这表明2 '，3'-cAMP参与大鼠脑线粒体中的PT调节。我们还发现，在PT开发下，CNP的比酶活性降低。因此，我们假设在阈值Ca 2+负荷下抑制CNP活性导致2 '，3'-cAMP水平升高，这反过来促进大鼠脑线粒体中PT的发育。在大鼠肝线粒体中观察到2 '，3'-环核苷酸的类似作用。在使用来自CNP敲低的少突胶质细胞（OLN 93细胞）的线粒体的实验中证实了CNP参与PT调节。这些线粒体中CNP的减少与降低Ca 2+超负荷诱导的Ca 2+释放阈值相关。因此，我们的结果揭示了CNP和2 '，3'-cAMP在线粒体中的新功能，作为线粒体PT的调节剂/促进剂。
Azarashvili T, Krestinina O, Galvita A, Grachev D, Baburina Y, Stricker R, Evtodienko Y, Reiser G. Ca2+-dependent permeability transition regulation in rat brain mitochondria by 2',3'-cyclic nucleotides and 2',3'-cyclic nucleotide 3'-phosphodiesterase. Am J Physiol Cell Physiol 296: C1428-C1439, 2009. First published April 8, 2009; doi:10.1152/ajpcell.00006.2009.-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.