ZINC REGULATION AND TOXICITY IN CELLULAR ENERGY METABOLI

描述(改编自申请人摘要)：这是第一次提交 锌在中枢神经系统毒性机制研究中的应用。近期 研究结果表明，在中风、创伤性脑损伤期间，这种阳离子升高 损伤和氧化应激，而细胞内锌的升高是 与培养神经元的死亡有关。升高的锌也与 线粒体功能障碍，以及细胞坏死和死亡 细胞凋亡，尽管这些作用的机制尚不清楚。调查员 和他的同事们最近的发现似乎与 锌在细胞水平上的毒性。他们发现亚微磨牙 锌浓度对线粒体α-酮戊二酸的抑制作用 脱氢酶和丙酮酸脱氢酶复合体，以及锌刺激 线粒体通透性转变。他们还指出，氧化应激 能从金属硫蛋白中释放出锌，金属硫蛋白表达 在大脑中与线粒体外膜有关。把所有的 综上所述，研究人员假设细胞损伤是由 氧化应激的产生，至少部分是因为锌从体内释放出来 金属硫蛋白在一个或两个水平上抑制TCA循环 脱氢酶，因此，或通过其他机制，激发 渗透性转变和随后的细胞死亡。开始评估这一点 假设，布朗博士将研究锌抑制细胞生长的机制。 脱氢酶的酶动力学和部分反应的研究。 线粒体转运锌的机制将被确定，并 将进行呼吸研究，以确定 锌对脱氢酶的作用，与电子传递链相比，在 造成线粒体功能障碍。最后，探讨了锌的作用机理。 渗透率转变的影响将被确定。在几个案例中 从大脑、心脏和肝脏线粒体获得的数据将与 确定调查结果的概括性，并允许交叉比较 文献，从这些发展到不同程度的线粒体 各种器官。

DESCRIPTION (Adapted from applicant's abstract):This is the first submission of an application to investigate the mechanism of Zn2+ toxicity in the CNS. Recent findings indicate that this cation is elevated during stroke, traumatic brain injury, and oxidative stress, and that elevated intracellular Zn2+ is associated with the death of cultured neurons. Elevated Zn2+ is also associated with mitochondrial dysfunction, and with the death of cells by necrosis and apoptosis, although the mechanism of these effects is unknown. The investigator and his associates have recent findings that seem to bear upon the mechanism of Zn2+ toxicity at the cellular level. They have found that submicromolar concentrations of Zn2+ inhibit the mitochondrial alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase complexes, and that Zn2+ stimulates the mitochondrial permeability transition. They also note that oxidative stress can release Zn2+ from metallothioneins and that the metallothionein expressed in brain is associated with the mitochondrial outer membrane. Putting all of this together, the investigator hypothesizes that cell injury caused by oxidative stress arises, at least in part, because Zn2+ is released from metallothionein, inhibits the TCA cycle at the level of one or both of the dehydrogenases, and thereby, or through other mechanisms, provokes the permeability transition and subsequent cell death. To begin evaluating this hypothesis, Dr. Brown will investigate the mechanism by which Zn2+ inhibits the dehydrogenases using enzyme kinetics and the study of partial reactions. Mechanisms transporting Zn2+ in mitochondria will be determined, and respiration studies will be conducted to ascertain the relative importance of Zn2+ action on the dehydrogenases, compared to the electron transport chain, in producing mitochondrial dysfunction. Finally, the mechanism by which Zn2+ influences the permeability transition will be determined. In several cases data obtained from brain, heart, and liver mitochondria will be compared, to ascertain the generality of the findings, and to allow a cross comparisons of literature, which is developed to different extents for mitochondria from these various organs.