ZINC REGULATION AND TOXICITY IN CELLULAR ENERGY METABOLI

描述（改编自申请人摘要）：这是首次提交的 应用于研究CNS中Zn 2+毒性的机制。最近 研究结果表明，这种阳离子在中风、创伤性脑 损伤和氧化应激，以及细胞内Zn 2+升高， 与培养的神经元死亡有关。Zn 2+也与 线粒体功能障碍，细胞坏死死亡， 细胞凋亡，虽然这些作用的机制是未知的。研究者 他和他的同事最近的发现似乎与 Zn 2+在细胞水平上的毒性。他们发现， 浓度的Zn 2+抑制线粒体α-酮戊二酸 脱氢酶和丙酮酸脱氢酶复合物，并且Zn 2+刺激 线粒体通透性转换。他们还指出， 能从金属硫蛋白中释放出Zn ~（2+）， 与线粒体外膜有关。把所有的 综上所述，研究人员假设， 氧化应激的产生，至少部分是因为Zn 2+从细胞中释放出来， 金属硫蛋白，在一个或两个水平上抑制TCA循环， 因此，或通过其他机制， 渗透性转变和随后的细胞死亡。开始评估这个 假设，布朗博士将研究锌2+抑制的机制， 利用酶动力学和部分反应的研究酶。 将确定线粒体中转运Zn 2+的机制， 将进行呼吸研究，以确定 与电子传递链相比， 产生线粒体功能障碍。最后，Zn 2 + 将确定渗透率转变的影响。在若干情况下 从脑、心脏和肝脏线粒体获得的数据将被比较， 确定调查结果的一般性，并允许交叉比较 文献，这是发展到不同程度的线粒体，从这些 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.