Rego A C, Ward M W, Nicholls D G
Buck Institute for Age Research, Novato, California 94945-1400, USA. .
J Neurosci. 2001 Mar 15;21(6):1893-901. doi: 10.1523/JNEUROSCI.21-06-01893.2001.
Although mitochondria mediate the delayed failure of cytoplasmic Ca(2+) homeostasis [delayed Ca(2+) deregulation (DCD)] in rat cerebellar granule cells resulting from chronic activation of NMDA receptors, their role in AMPA/KA-induced DCD remains to be established. The mitochondrial ATP synthase inhibitor oligomycin protected cells against KA- but not NMDA-evoked DCD. In contrast to NMDA-evoked DCD, no additional protection was afforded by the further addition of rotenone. The effects of KA on cytoplasmic Ca(2+) homeostasis, including the protection afforded by oligomycin, could be reproduced by veratridine. KA exposure induced a partial mitochondrial depolarization that was enhanced by oligomycin, indicating ATP synthase reversal. The nonglycolytic substrates pyruvate and lactate were unable to maintain Ca(2+) homeostasis in the presence of KA. In contrast to NMDA, KA exposure did not cause mitochondrial Ca(2+) loading. The data indicate that Na(+) entry via noninactivating AMPA/KA receptors or voltage-activated Na(+) channels compromises mitochondrial function sufficiently to cause ATP synthase reversal. Oligomycin may protect by preventing the consequent mitochondrial drain of cytoplasmic ATP.
尽管线粒体介导了大鼠小脑颗粒细胞中因NMDA受体慢性激活导致的细胞质Ca(2+)稳态延迟性衰竭[延迟性Ca(2+)去调节（DCD）]，但其在AMPA/KA诱导的DCD中的作用仍有待确定。线粒体ATP合酶抑制剂寡霉素可保护细胞免受KA诱发的DCD影响，但对NMDA诱发的DCD无效。与NMDA诱发的DCD不同，再添加鱼藤酮并不能提供额外的保护。藜芦碱可重现KA对细胞质Ca(2+)稳态的影响，包括寡霉素提供的保护作用。KA暴露诱导了部分线粒体去极化，寡霉素可增强这种去极化，表明ATP合酶发生了逆转。在存在KA的情况下，非糖酵解底物丙酮酸和乳酸无法维持Ca(2+)稳态。与NMDA不同，KA暴露不会导致线粒体Ca(2+)负载。数据表明，通过非失活的AMPA/KA受体或电压激活的Na(+)通道进入的Na(+)足以损害线粒体功能，从而导致ATP合酶逆转。寡霉素可能通过防止随后线粒体对细胞质ATP的消耗来提供保护。
