Linking Mitochondrial Dysfunction to Organismal and Population Health in the Context of Environmental Pollutants: Progress and Considerations for Mitochondrial Adverse Outcome Pathways
Linking Mitochondrial Dysfunction to Organismal and Population Health in the Context of Environmental Pollutants: Progress and Considerations for Mitochondrial Adverse Outcome Pathways
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DOI：
10.1002/etc.4453
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发表时间：
2019-08-01
影响因子：
4.1
通讯作者：
Martyniuk, Christopher J.
中科院分区：
文献类型：
--
作者：
Dreier, David A.;Mello, Danielle F.;Martyniuk, Christopher J.
线粒体是许多环境污染物的关键目标，因为特定的化学物质可以直接与线粒体蛋白、脂质和核糖核酸相互作用。这些直接的相互作用作为分子启动事件，阻碍三磷酸腺苷的产生和线粒体在细胞内服务的其他关键功能（例如钙和金属稳态、细胞凋亡、免疫信号传导、氧化还原平衡）。有限但数量不断增加的不良结果通路（AOPs）已被提出将线粒体功能障碍与机体和群体水平的影响联系起来。这些途径包括膜电位改变、线粒体裂变/融合和线粒体DNA损伤等关键事件。本综述和分析揭示了涉及线粒体功能障碍的AOPs的最新进展，并使用基于网络的计算方法，确定了多个现有AOPs中线粒体分子启动事件和关键事件的定位。我们还提出了两个案例研究，第一个研究线粒体和免疫毒性之间的相互作用，第二个研究早期线粒体功能障碍在行为（即运动活动）背景下的作用。我们讨论了我们目前对线粒体AOPs的理解的局限性，并强调了澄清其细节的机会。在AOP框架内推进我们对关键事件关系的知识将需要高吞吐量的数据集，这些数据集允许开发和测试与化学无关的AOP，还需要高分辨率的研究，这将增强这些关键事件关系的机制测试和验证。考虑到影响线粒体的化学物质范围广泛，以及能量产生和信号传导对生态重要结果（如病原体防御、体内平衡、生长和繁殖）的中心地位，更好地了解线粒体AOPs有望在环境毒理学中发挥重要作用，即使不是核心作用。环境科学与技术，2019;38(1):1 - 4。(c) 2019 SETAC
Mitochondria are key targets of many environmental contaminants, because specific chemicals can interact directly with mitochondrial proteins, lipids, and ribonucleic acids. These direct interactions serve as molecular initiating events that impede adenosine triphosphate production and other critical functions that mitochondria serve within the cell (e.g., calcium and metal homeostasis, apoptosis, immune signaling, redox balance). A limited but growing number of adverse outcome pathways (AOPs) have been proposed to associate mitochondrial dysfunction with effects at organismal and population levels. These pathways involve key events such as altered membrane potential, mitochondrial fission/fusion, and mitochondrial DNA damage, among others. The present critical review and analysis reveals current progress on AOPs involving mitochondrial dysfunction, and, using a network-based computational approach, identifies the localization of mitochondrial molecular initiating events and key events within multiple existing AOPs. We also present 2 case studies, the first examining the interaction between mitochondria and immunotoxicity, and the second examining the role of early mitochondrial dysfunction in the context of behavior (i.e., locomotor activity). We discuss limitations in our current understanding of mitochondrial AOPs and highlight opportunities for clarifying their details. Advancing our knowledge of key event relationships within the AOP framework will require high-throughput datasets that permit the development and testing of chemical-agnostic AOPs, as well as high-resolution research that will enhance the mechanistic testing and validation of these key event relationships. Given the wide range of chemicals that affect mitochondria, and the centrality of energy production and signaling to ecologically important outcomes such as pathogen defense, homeostasis, growth, and reproduction, a better understanding of mitochondrial AOPs is expected to play a significant, if not central, role in environmental toxicology. Environ Toxicol Chem 2019;38:1625-1634. (c) 2019 SETAC