Modulation of reactive oxygen species and redox homeostasis by environmental stress

为了有效地测量多种应激源对生物系统的交互效应，需要识别和表征一种综合多种应激源引起的反应的敏感效应指标。我之前的研究表明，作用于线粒体的氧化应激可能有助于整合多种应激源的作用。因此，我建议探讨不同的环境应激源诱导活性氧（ROS）导致氧化应激，从而损害线粒体和细胞功能，导致机体性能和适应性降低或死亡。我将用鱼和三种常见的水生系统压力源来测试这个想法：金属、温度和缺氧。为了避免由于调查有限的端点而导致先前研究结果不确定的缺点，我将采用整体方法，从多个角度询问ROS稳态。首先，我将描述线粒体和细胞ROS代谢和氧化还原调节，并揭示它们是如何被应激源调节的。其次，我将研究环境应激源及其相互作用如何影响线粒体稳态，以及活性氧的作用。第三，我将探讨环境压力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，以及它们的功能后果。总的来说，这项研究将从根本上促进我们对线粒体生理学和氧化应激反应的理解。重要的是，这项研究将推进我们对环境应激源如何调节活性氧的多种作用的认识，活性氧被认为是动物许多生理和病理状态的基础。实际上，增加对压力源组合如何影响水生生物适应性的理解将有助于更好地预测和更有效地管理其环境影响。

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.