Molecular components of the mitochondrial permeability transition pore and its role in neurodegenerative diseases
线粒体通透性转换孔的分子组成及其在神经退行性疾病中的作用
基本信息
- 批准号:10553396
- 负责人:
- 金额:$ 7.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-07-15 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Project Summary/Abstract
Mitochondrial and synaptic dysfunction are early pathological features of Alzheimer's
disease (AD) and other neurodegenerative diseases. The mitochondrial permeability transition
pore (mPTP) is a mitochondrial ion channel that plays a central role in cell death during age-
related neurodegeneration, therefore mPTP can serve as an important therapeutic target.
Studies show that the major mPTP inducer, the peptidylprolyl isomerase cyclophilin D (CypD),
interacts directly with the OSCP subunit of the stator arm of the mammalian ATP synthase. The
stator arm stabilizes the connection between the ATP synthase catalytic (F1) and membrane
(FO) portions. In AD, a complex of CypD and oligomeric Aβ peptide have been found to
potentiate mPTP opening, resulting in impaired mitochondrial function, neuronal injury and
death.
We have recently suggested a novel role of the ATP synthase membrane embedded c-
subunit in forming the pore of mPT. We have found further that the F1 portion of the ATP
synthase gates the channel and that the loss of F1 components and OSCP during glutamate-
induced excitotoxicity is correlated with neuronal death. We suggest that disruptions in
interaction between the F1 and the stator arm during neuronal toxicity destabilize the ATP
synthase structure, making the mitochondria more susceptible to mPT and cell death.
In this proposal, using mutagenesis, we will investigate the molecular mechanisms that
lead to the opening of the c-subunit leak channel, which converts the ATP synthase from an
energy-conserving to an energy-dissipating, cell death-inducing, device. In order to attempt to
enhance neuronal survival in the face of stress, we will perform mutations within the ATP
synthase that modify the conformation of the ATP synthase, preventing mPT channel gating and
decreasing channel conductance. Based on our mutagenesis findings we will design a
transgenic mouse on the background of the AD model (Tg mAPP) mouse to study if
neuroprotective ATP synthase mutations will protect the Tg mAPP mouse from the onset of AD-
like features. We will also introduce the same mutations in non transgenic mouse to study the
physiological roles of mPTP in the cell in general.
Identifying molecular mechanisms underlying c-subunit gating will provide us with
increased understanding of the role of mPTP in aging and neurodegeneration. The findings will
lead to the design of specific and potent therapeutic compounds to target the mPTP directly,
resulting in preventative strategies for neurodegenerative disease.
项目摘要/摘要
线粒体和突触功能障碍是阿尔茨海默病的早期病理特征
阿尔茨海默病(AD)和其他神经退行性疾病。线粒体通透性转换
毛孔(MPTP)是一种线粒体离子通道,在衰老过程中细胞死亡中发挥核心作用。
相关的神经变性,因此MPTP可以作为一个重要的治疗靶点。
研究表明,MPTP的主要诱导物是环磷酰异构酶D(CypD),
直接与哺乳动物ATP合成酶定子臂的OSCP亚单位相互作用。这个
定子臂稳定三磷酸腺苷合成酶催化(F1)与膜的连接
(F)部分。在AD中,CypD与寡聚体Aβ多肽的复合体被发现
增强MPTP开放,导致线粒体功能受损,神经元损伤和
死亡。
我们最近提出了一种新的作用,即嵌入c-ATP合成酶的膜。
形成MPT孔道的亚基。我们进一步发现,<English>ATP</English>的<English>F</English>一部分
合成酶对该通道进行门控,而F1组分和OSCP的丢失在谷氨酸-
诱发的兴奋性毒性与神经元死亡有关。我们认为,
神经元毒性过程中F1与定子臂的相互作用破坏ATP的稳定性
合酶结构,使线粒体更容易受到MPT和细胞死亡的影响。
在这项提议中,我们将利用突变技术来研究
导致c-亚基泄漏通道的打开,它将ATP合成酶从一个
节能到一种能量耗散、细胞死亡诱导的装置。为了试图
提高神经元的存活率面对应激,我们会在ATP内部进行突变
改变ATP合成酶构象的合酶,防止MPT通道门控和
降低通道电导。根据我们的诱变发现,我们将设计一种
以转基因小鼠为背景建立AD模型(TG-MAPP)小鼠,研究其是否
神经保护性ATP合酶突变将保护TG Mapp小鼠免受AD-
就像功能一样。我们还将在非转基因小鼠中引入相同的突变,以研究
MPTP在细胞中的一般生理作用。
识别c亚基门控的分子机制将为我们提供
进一步了解MPTP在衰老和神经退行性变中的作用。调查结果将
导致设计出直接针对MPTP的特定和有效的治疗化合物,
导致了神经退行性疾病的预防策略。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
ATP synthase c-subunit ring as the channel of mitochondrial permeability transition: Regulator of metabolism in development and degeneration.
- DOI:10.1016/j.yjmcc.2020.05.013
- 发表时间:2020-07
- 期刊:
- 影响因子:5
- 作者:Mnatsakanyan N;Jonas EA
- 通讯作者:Jonas EA
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Nelli Mnatsakanyan的其他文献
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{{ truncateString('Nelli Mnatsakanyan', 18)}}的其他基金
Structural and functional characterization of ATP synthase c-subunit leak channel and its role in AD pathogenesis
ATP合酶c亚基泄漏通道的结构和功能特征及其在AD发病机制中的作用
- 批准号:
10553483 - 财政年份:2021
- 资助金额:
$ 7.58万 - 项目类别:
Structural and functional characterization of ATP synthase c-subunit leak channel and its role in AD pathogenesis
ATP合酶c亚基泄漏通道的结构和功能特征及其在AD发病机制中的作用
- 批准号:
10214094 - 财政年份:2021
- 资助金额:
$ 7.58万 - 项目类别:
Molecular components of the mitochondrial permeability transition pore and its role in neurodegenerative diseases
线粒体通透性转换孔的分子组成及其在神经退行性疾病中的作用
- 批准号:
9905337 - 财政年份:2017
- 资助金额:
$ 7.58万 - 项目类别:
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