Mitochondrial ROS microdomains and neuronal ischemia

线粒体 ROS 微区和神经元缺血

基本信息

  • 批准号:
    10552598
  • 负责人:
  • 金额:
    $ 39.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-07-01 至 2026-01-31
  • 项目状态:
    未结题

项目摘要

Project Summary Reactive oxygen species (ROS) contribute to pathology, but conversely, in limited measure they can also act as second messengers, whereby they contribute to beneficial cellular signaling. Similar to calcium signaling or other second messengers, the precise location, timing, and duration of ROS production likely determine divergent signaling outputs. The mechanism underlying this functional dichotomy in redox biology is currently under studied. An intriguing example of an apparent paradoxical impact of ROS occurs at complex I of the mitochondrial electron transport chain. In the case of detrimental effects of oxidation, mitochondrial complex I ROS production is mechanistically linked to oxidative damage in ischemia reperfusion (IR) injury, the pathology of stroke. In the case of beneficial signaling, complex I ROS production is implicated in protective hypoxic signaling. Indeed, the fact that some ROS production is a normal consequence of mitochondrial respiration supports the idea that ROS contribute to normal physiology. Therefore, describing the nuances of complex I ROS production and its context- dependent metabolic effects is necessary to fully determine the mechanisms of mitochondrial redox signaling, both damaging and physiologic. To achieve that goal, precise experimental control of ROS production is required. Until recently, controlling ROS production as an independent variable has been difficult. This renewal leverages an optogenetic approach championed by our lab to overcome this barrier, and isolates ROS production at complex I in the genetic model organism C. elegans. Previously, we have shown that ROS production at the complex II microdomain differentially affects redox-sensitive outcomes in models of IR injury, depending on whether the ROS were produced inside the mitochondrial matrix or in the intermembrane space. Using our published novel CRISPR/Cas9 technology optimized for rapid use in C. elegans, we will target well-characterized light-activated ROS generating proteins (RGPs) to endogenous complex I in order to precisely control the location, timing, and duration of complex I ROS production with light. This will provide a model of either complex I redox signaling, or oxidative damage, depending on the light-titration of RGP activation, where more light will produce more ROS. Combined with tissue-specific expression, we will determine the effects of each of these spatiotemporal parameters on normal mitochondrial function, neuronal function, and stress-resistance signaling programs in response to simulated IR injury. We will focus on the neuronal outcomes of complex I ROS production, both in response to strong literature support for the importance of neurons in mediating hypoxic stress signaling, and to determine neuronal circuits that could be targeted for translation to mammalian models of stroke. This approach is perfectly suited to the powerful C. elegans genetic system. We expect that completion of our aims will provide novel, fundamental insights with clear answers to questions about how the mitochondrial complex I ROS microdomain controls diverse outcomes in both disease and physiology.
项目总结

项目成果

期刊论文数量(0)
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专利数量(0)

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Andrew Phillip Wojtovich其他文献

Andrew Phillip Wojtovich的其他文献

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{{ truncateString('Andrew Phillip Wojtovich', 18)}}的其他基金

Mitochondrial Energy Sensing and Neuronal Ischemia
线粒体能量感应和神经元缺血
  • 批准号:
    10524047
  • 财政年份:
    2020
  • 资助金额:
    $ 39.81万
  • 项目类别:
Mitochondrial Energy Sensing and Neuronal Ischemia
线粒体能量感应和神经元缺血
  • 批准号:
    10090662
  • 财政年份:
    2020
  • 资助金额:
    $ 39.81万
  • 项目类别:
Mitochondrial Energy Sensing and Neuronal Ischemia
线粒体能量感应和神经元缺血
  • 批准号:
    10318080
  • 财政年份:
    2020
  • 资助金额:
    $ 39.81万
  • 项目类别:
Mitochondrial ROS microdomains and neuronal ischemia
线粒体 ROS 微区和神经元缺血
  • 批准号:
    10198294
  • 财政年份:
    2015
  • 资助金额:
    $ 39.81万
  • 项目类别:
Mitochondrial ROS microdomains and neuronal ischemia
线粒体 ROS 微区和神经元缺血
  • 批准号:
    9277588
  • 财政年份:
    2015
  • 资助金额:
    $ 39.81万
  • 项目类别:
Mitochondrial ROS microdomains and neuronal ischemia
线粒体 ROS 微区和神经元缺血
  • 批准号:
    10337338
  • 财政年份:
    2015
  • 资助金额:
    $ 39.81万
  • 项目类别:
Mitochondrial ROS microdomains and neuronal ischemia
线粒体 ROS 微区和神经元缺血
  • 批准号:
    9059782
  • 财政年份:
    2015
  • 资助金额:
    $ 39.81万
  • 项目类别:

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