Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria
Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria
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DOI：
10.1073/pnas.93.18.9893
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发表时间：
1996-09-03
影响因子：
11.1
通讯作者：
Fiskum, G
中科院分区：
文献类型：
--
作者：
Murphy, AN;Bredesen, DE;Fiskum, G
人类原癌基因bcl-2的表达保护神经细胞免受多种应激形式引起的死亡，包括细胞内Ca2+水平大幅升高的条件。考虑到Bcl-2部分定位于线粒体膜，并且过量的线粒体Ca2+摄取会损害电子传递和氧化磷酸化，本研究验证了一个假设，即来自表达Bcl-2的细胞的线粒体具有更高的能量依赖性Ca2+摄取能力，并且比来自不表达该蛋白的细胞的线粒体更能抵抗Ca2+诱导的呼吸损伤。当谷氨酸和苹果酸盐作为呼吸底物时，bcl-2的过表达使地黄皂苷渗透的GT1-7神经细胞或分离的GT1-7线粒体的线粒体Ca2+摄取能力分别提高了1.7倍和3.9倍。当呼吸作用在呼吸复合体I抑制剂鱼藤酮的存在下由琥珀酸的氧化所驱动时，这种差异就不那么明显了。来自Bcl-2表达者的线粒体也更能抵抗由大量Ca2+负载的隔离引起的nadh依赖性呼吸的抑制。表达Bcl-2的细胞内线粒体隔绝大量Ca2+而不发生严重呼吸损伤的能力增强，为Bcl-2抑制某些形式的延迟细胞死亡（包括与缺血和兴奋性毒性相关的神经元死亡）提供了一种合理的机制。
Expression of the human protooncogene bcl-2 protects neural cells from death induced by many forms of stress, including conditions that greatly elevate intracellular Ca2+. Considering that Bcl-2 is partially localized to mitochondrial membranes and that excessive mitochondrial Ca2+ uptake can impair electron transport and oxidative phosphorylation, the present study tested the hypothesis that mitochondria from Bcl-2-expressing cells have a higher capacity for energy-dependent Ca2+ uptake and a greater resistance to Ca2+-induced respiratory injury than mitochondria from cells that do not express this protein. The overexpression of bcl-2 enhanced the mitochondrial Ca2+ uptake capacity using either digitonin-permeabilized GT1-7 neural cells or isolated GT1-7 mitochondria by 1.7 and 3.9 fold, respectively, when glutamate and malate were used as respiratory substrates. This difference was less apparent when respiration was driven by the oxidation of succinate in the presence of the respiratory complex I inhibitor rotenone. Mitochondria from Bcl-2 expressors were also much more resistant to inhibition of NADH-dependent respiration caused by sequestration of large Ca2+ loads. The enhanced ability of mitochondria within Bcl-2-expressing cells to sequester large quantities of Ca2+ without undergoing profound respiratory impairment provides a plausible mechanism by which Bcl-2 inhibits certain forms of delayed cell death, including neuronal death associated with ischemia and excitotoxicity.