Bax regulates production of superoxide in both apoptotic and nonapoptotic neurons: role of caspases.
Bax regulates production of superoxide in both apoptotic and nonapoptotic neurons: role of caspases.
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DOI：
10.1523/jneurosci.2862-10.2010
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发表时间：
2010-12-01
期刊：
影响因子：
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通讯作者：
Franklin JL
中科院分区：
文献类型：
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作者：
Kirkland RA;Saavedra GM;Cummings BS;Franklin JL
在凋亡的颈上神经节（SCG）和小脑颗粒（CG）神经元中，Bax和线粒体依赖性的超氧化物（O2.−）和其他活性氧（ROS）增加。在这里，我们发现Bax也位于非凋亡神经元产生的ROS的上游，并提供了半胱天冬酶部分介导Bax的促氧化作用的证据。我们用了O2。−敏感染料MitoSOX监测O2。−在表达不同水平Bax和线粒体超氧化物歧化酶（SOD2）的神经元中。基础和凋亡O2。在Bax浓度较低的SOD2野生型（wt）细胞中，SCG和CG神经元中的−水平均降低。Bax-wt/SOD2-null小鼠的凋亡和非凋亡神经元均有O2升高，而Bax-wt/SOD2-null小鼠的O2升高。−水平。caspase抑制剂抑制O2。−在凋亡和非凋亡的SCG神经元中均存在。O2。经活化caspase - 3处理后，−的产生增加，但Bax-null SCG神经元不增加。无细胞凋亡，氧含量升高。−caspase 3缺失小鼠的SCG神经元暴露于凋亡刺激。O2。非凋亡caspase 3-null SCG神经元中的−水平低于wt细胞，但不低于caspase抑制剂处理的细胞。这些数据表明Bax位于大多数O2的上游。-在神经元中产生，caspase 3是增加氧气所必需的。−在神经元凋亡过程中产生，caspase 3部分参与O2。−在非凋亡神经元中产生，其他caspase也可能参与bax依赖性O2。−在非凋亡细胞中产生。
A Bax- and, apparently, mitochondria-dependent increase in superoxide (O2.−) and other reactive oxygen species (ROS) occurs in apoptotic superior cervical ganglion (SCG) and cerebellar granule (CG) neurons. Here we show that Bax also lies upstream of ROS produced in nonapoptotic neurons and present evidence that caspases partially mediate the pro-oxidant effect of Bax. We used the O2.−-sensitive dye MitoSOX to monitor O2.− in neurons expressing different levels of Bax and mitochondrial superoxide dismutase (SOD2). Basal and apoptotic O2.− levels in both SCG and CG neurons were reduced in SOD2 wild-type (wt) cells having lower Bax concentrations. Apoptotic and nonapoptotic neurons from Bax-wt/SOD2-null but not Bax-null/SOD2-null mice had increased O2.− levels. A caspase inhibitor inhibited O2.− in both apoptotic and nonapoptotic SCG neurons. O2.− production increased when wt, but not Bax-null SCG neurons were permeabilized and treated with active caspase 3. There was no apoptosis and little increase in O2.− in SCG neurons from caspase 3-null mice exposed to an apoptotic stimulus. O2.− levels in nonapoptotic caspase 3-null SCG neurons were lower than in wt cells but not as low as in caspase inhibitor-treated cells. These data indicate that Bax lies upstream of most O2.− produced in neurons, that caspase 3 is required for increased O2.− production during neuronal apoptosis, that caspase 3 is partially involved in O2.− production in nonapoptotic neurons, and that other caspases may also be involved in Bax-dependent O2.− production in nonapoptotic cells.