Modulation of reactive oxygen species and redox homeostasis by environmental stress

为了有效地衡量多种应激源对生物系统的交互影响，需要确定和表征一个敏感的效应指标，该指标整合了不同应激源引起的反应。我之前的研究表明，作用于线粒体的氧化应激在整合多种应激源的影响方面可能是有用的。因此，我建议探讨不同的环境应激源诱导活性氧物种(ROS)导致氧化应激，从而损害线粒体和细胞功能，从而降低生物体的性能和适合度，甚至死亡。我将使用FISH和水生系统的三个常见和相应的应激源来测试这一想法：金属、温度和缺氧。为了避免以往研究因调查有限的终点而导致不确定结果的缺点，我将采用整体方法，从多个角度询问ROS动态平衡。首先，我将描述线粒体和细胞的ROS代谢和氧化还原调节，并揭示它们是如何受应激源调节的。其次，我将研究环境应激源及其交互作用如何影响线粒体的动态平衡，以及ROS的作用。第三，我将探索环境应激源如何调节不同线粒体功能特性之间的关系。第四，我将探讨ROS诱导的分子反应和氧化修饰，包括它们是如何被环境应激源调节的，以及由此产生的功能后果。总体而言，拟议的研究将从根本上有助于我们理解线粒体生理学和氧化应激反应。重要的是，这项研究将促进我们对环境应激源如何调节ROS的各种影响的了解，ROS被认为是动物许多生理和病理状态的基础。在实践中，更多地了解应激源组合如何影响水生生物的适合性将导致对其环境影响的更好预测和更有效的管理。

To effectively measure the interactive effects of multiple stressors on biological systems, a sensitive indicator of effects that integrates the responses induced by diverse stressors needs to be identified and characterized. My previous research suggests that oxidative stress acting on the mitochondria may be useful in integrating effects of multiple stressors. I therefore propose to probe the idea that diverse environmental stressors induce reactive oxygen species (ROS) leading to oxidative stress that impairs mitochondrial and cellular functions resulting in reduction in performance and fitness or death of the organism. I will test this idea using fish and three common and consequential stressors of aquatic systems: metals, temperature and hypoxia. To avoid shortcomings of previous research that have resulted in inconclusive findings because of investigating a limited number of endpoints, I will employ a holistic approach and interrogate ROS homeostasis from multiple angles. First, I will characterize mitochondrial and cellular ROS metabolism and redox regulation, and unveil how they are modulated by stressors. Second, I will examine how environmental stressors and their interactive effects influence mitochondrial homeostasis, and the role of ROS. Third, I will explore how environmental stressors modulate the relationship among different mitochondrial functional properties. Fourth, I will probe the molecular responses and oxidative modifications induced by ROS including how they are modulated by environmental stressors, and the functional consequences thereof. Overall, the proposed research will contribute fundamentally to our understanding of mitochondrial physiology and the oxidative stress response. Importantly, this research will advance our knowledge of how environmental stressors modulate the diverse effects of ROS that are believed to be the basis of many physiological and pathological states in animals. In practical terms, increased understanding of how combinations of stressors affect fitness of aquatic organisms will lead to better prediction and more effective management of their environmental impacts.