Role of Bcl-xL in neuronal mitochondrial calcium dynamics

Bcl-xL 在神经元线粒体钙动力学中的作用

基本信息

  • 批准号:
    8604982
  • 负责人:
  • 金额:
    $ 24.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-07-01 至 2015-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial dysfunction has been associated with many neurodegenerative disorders including Alzheimer's Disease (AD) and Parkinson's Disease (PD). Mitochondrial dynamics and axonal trafficking are required for synaptogenesis and synaptic strengthening. It is proposed that mitochondria may act as local sources of ATP or as sites of presynaptic calcium buffering and re- release during synaptic plasticity and that these processes could be altered in neurodegenerative disease. However, the mechanisms of how mitochondria meet the high energy demands and calcium buffering requirements during synaptic plasticity are incompletely studied. Mitochondrial permeability transition pore (mPTP) activity is critical to determining inner membrane permeability and cell death under pathological conditions. However, very little is known regarding physiological function of the calcium-regulated inner membrane permeability transition pore during synaptic transmission. We reported previously that an unknown channel governs mitochondrial ion channel activity that is necessary for short term synaptic plasticity in response to high frequency synaptic activity. This mitochondrial channel activity is inhibited by the small molecule Bcl-xL inhibitor ABT- 737 and ABT-737 also attenuates synaptic function. Recently we found that Bcl-xL localizes to mitochondrial inner membrane and interacts with the F1FO ATP synthase; the interaction is required to prevent proton leak through an inner membrane channel and to regulate ATP production. Our preliminary data suggest that the non-selective ion channel affected by Bcl-xL is the mitochondrial permeability transition pore (mPTP) and that it is located within the c-subunit of the FO of the ATP synthase. We therefore hypothesize that during synaptic transmission, Bcl-xL translocates to the mitochondrial inner membrane and improves mPTP gating to enhance the degree of mitochondrial calcium efflux following intense synaptic events. In the absence of Bcl-xL the pore will not open properly, and defects in calcium efflux from mitochondria will occur. These defects may contribute to a loss of synaptic plasticity.
描述(由申请人提供):线粒体功能障碍与许多神经退行性疾病相关,包括阿尔茨海默病(AD)和帕金森病(PD)。线粒体动力学和轴突运输是突触发生和突触强化所必需的。有人提出,线粒体可能作为ATP的局部来源或作为突触前钙缓冲和突触可塑性期间再释放的位点,并且这些线粒体可能是突触前钙缓冲和突触可塑性期间再释放的位点。 在神经退行性疾病中可能发生改变。然而,线粒体如何满足突触可塑性过程中的高能量需求和钙缓冲需求的机制尚未完全研究。线粒体通透性转换孔(mPTP)活性是决定内膜通透性和病理条件下细胞死亡的关键。然而,很少有人知道关于生理功能的钙调节内膜通透性转换孔在突触传递。我们先前报道了一个未知的通道支配线粒体离子通道的活动,这是必要的短期突触可塑性,以响应高频突触活动。这种线粒体通道活性被小分子Bcl-xL抑制剂ABT- 737抑制,并且ABT-737也减弱突触功能。最近我们发现Bcl-xL定位于线粒体内膜并与F1 FO ATP合酶相互作用;这种相互作用是防止质子通过内膜通道泄漏和调节ATP产生所必需的。我们的初步数据表明,受Bcl-xL影响的非选择性离子通道是线粒体通透性转换孔(mPTP),它位于ATP合酶FO的c-亚基内。因此,我们假设在突触传递过程中,Bcl-xL易位到线粒体内膜,并改善mPTP门控,以提高线粒体钙外流的程度后,强烈的突触事件。在缺乏Bcl-xL的情况下,孔将不能正常打开,并且将发生线粒体钙流出的缺陷。这些缺陷可能导致突触可塑性的丧失。

项目成果

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Kambiz Nassirpour Alavian其他文献

Kambiz Nassirpour Alavian的其他文献

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{{ truncateString('Kambiz Nassirpour Alavian', 18)}}的其他基金

Mitochondrial control of protein translation in Fragile X
脆性 X 蛋白翻译的线粒体控制
  • 批准号:
    10379427
  • 财政年份:
    2019
  • 资助金额:
    $ 24.98万
  • 项目类别:
Mitochondrial control of protein translation in Fragile X
脆性 X 蛋白翻译的线粒体控制
  • 批准号:
    10599936
  • 财政年份:
    2019
  • 资助金额:
    $ 24.98万
  • 项目类别:
Role of Bcl-xL in neuronal mitochondrial calcium dynamics
Bcl-xL 在神经元线粒体钙动力学中的作用
  • 批准号:
    8688373
  • 财政年份:
    2013
  • 资助金额:
    $ 24.98万
  • 项目类别:

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