Regulation of mitochondrial calcium signaling by Pannexin2

Pannexin2 对线粒体钙信号传导的调节

• 批准号: RGPIN-2016-05471
• 负责人: Naus, Christian
• 金额: $ 2.77万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=615714
• 关键词: Regulation; mitochondrial; calcium; signaling; Pannexin2

Pannexins are channel proteins that are related to the connexin family of gap junction proteins. Unlike connexins, pannexins do not from a link between two adjacent cells but connect directly to the external environment of the cells. However, we recently showed that one member of the pannexins, Panx2, is restricted to the interior of the cell. Most importantly, it is closely associated with mitochondria, the energy powerhouse of the cell. Defects in mitochondria are implicated in brain disorders including Alzheimer’s and Parkinson’s disease. Since pannexin channels have been reported to be permeable to calcium ions, we hypothesize that under normal conditions Panx2 channel activity regulate mitochondrial energy production by regulating mitochondrial calcium levels. In contrast, under pathological conditions, dysregulation of Panx2 channel activity triggers mitochondrial calcium overload leading to cell death. We propose to test this hypothesis in three interrelated aims. In Aim 1, we will examine whether alteration of mitochondrial energy production will lead to changes in Panx2 expression and distribution. If an increase in Panx2 is related to mitochondrial dysfunction, we will determine whether Panx2 modulates the production of energy molecule ATP in Aim 2. After confirming the critical role of Panx2 in mitochondrial signaling, we will investigate whether Panx2 activity influences the level mitochondrial calcium in Aim 3. Findings from our proposal will reveal novel strategies to curtail mitochondrial dysfunction and lay the foundation of possible therapeutic interventions in brain diseases.

Pannexin是一种通道蛋白，它是 与缝隙连接蛋白的连接蛋白家族相关。与缝隙连接蛋白不同，Pannexins 不要从两个相邻电池之间的链路直接连接到外部 细胞的环境。然而，我们最近表明，委员会的一名成员 Pannexins，Panx2，仅限于细胞内部。最重要的是， 它与线粒体密切相关，线粒体是细胞的能量源泉。线粒体的缺陷牵涉到 包括阿尔茨海默氏症和帕金森氏症在内的大脑疾病。自Pannexin以来 据报道，通道对钙离子具有通透性，我们推测 在正常情况下Panx2通道活性调节线粒体 通过调节线粒体钙水平来产生能量。相比之下， 在病理条件下，Panx2通道活动的失调触发 线粒体钙超载导致细胞死亡。我们建议对此进行测试 三个相互关联的目标中的假设。在目标1中，我们将研究 线粒体能量产生的改变将导致Panx2的变化 表达和分布。如果Panx2的增加与 线粒体功能障碍，我们将确定Panx2是否调节 能量分子三磷酸腺苷在AIM中的生产2.在确认关键作用后 关于Panx2在线粒体信号中的作用，我们将研究Panx2的活性 影响AIM 3的线粒体钙水平。我们建议的结果 将揭示减少线粒体功能障碍的新策略，并为 为脑部疾病可能的治疗干预奠定基础。