Nicholls D G, Budd S L
Neurosciences Institute, Department of Pharmacology and Neuroscience, University of Dundee, Dundee DD1 9SY, UK.
Biochim Biophys Acta. 1998 Aug 10;1366(1-2):97-112. doi: 10.1016/s0005-2728(98)00123-6.
The role of mitochondria in the control of glutamate excitotoxicity is investigated. The response of cultured cerebellar granule cells to continuous glutamate exposure is characterised by a transient elevation in cytoplasmic free calcium concentration followed by decay to a plateau as NMDA receptors partially inactivate. After a variable latent period, a secondary, irreversible increase in calcium occurs (delayed calcium deregulation, DCD) which precedes and predicts subsequent cell death. DCD is not controlled by mitochondrial ATP synthesis since it is unchanged in the presence of the ATP synthase inhibitor oligomycin in cells with active glycolysis. However, mitochondrial depolarisation (and hence inhibition of mitochondrial calcium accumulation) without parallel ATP depletion (oligomycin plus either rotenone or antimycin A) strongly protects the cells against DCD. Glutamate exposure is associated with an increase in the generation of superoxide anion by the cells, but superoxide generation in the absence of mitochondrial calcium accumulation is not neurotoxic. While it is concluded that mitochondrial calcium accumulation plays a critical role in the induction of DCD we can find no evidence for the involvement of the mitochondrial permeability transition.
研究了线粒体在控制谷氨酸兴奋性毒性中的作用。培养的小脑颗粒细胞对持续谷氨酸暴露的反应特征为细胞质游离钙浓度短暂升高，随后随着NMDA受体部分失活而衰减至平台期。在可变的潜伏期后，会出现继发性、不可逆的钙增加（延迟性钙失调，DCD），其先于并预示随后的细胞死亡。DCD不受线粒体ATP合成的控制，因为在具有活跃糖酵解的细胞中，存在ATP合酶抑制剂寡霉素时，DCD没有变化。然而，线粒体去极化（从而抑制线粒体钙积累）而没有平行的ATP耗竭（寡霉素加鱼藤酮或抗霉素A）能强烈保护细胞免受DCD影响。谷氨酸暴露与细胞超氧阴离子生成增加有关，但在没有线粒体钙积累的情况下超氧生成没有神经毒性。虽然得出结论线粒体钙积累在DCD的诱导中起关键作用，但我们没有发现线粒体通透性转换参与的证据。
