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

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.
项目总结/文摘

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.
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Nelli Mnatsakanyan其他文献

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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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
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    9905337
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    $ 7.58万
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探索 TSEN 在神经元发育和维持中的线粒体功能
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Exploring the mitochondrial function of TSEN in neuronal development and maintenance
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线粒体周转的机制和成分以及线粒体自噬的质量控制
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Elucidating the molecular mechanisms regulating embryonic cardiac rhythmicity
阐明调节胚胎心律的分子机制
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    8223164
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    2010
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Elucidating the molecular mechanisms regulating embryonic cardiac rhythmicity
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    7889281
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    8424959
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    2010
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