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Environ Toxicol Chem. 2019 Apr 29. doi: 10.1002/etc.4453. [Epub ahead of print]

Linking mitochondrial dysfunction to organismal and population health in context of environmental pollutants: Progress and considerations for mitochondrial adverse outcome pathways.

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Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA.
Nicholas School of the Environment, Duke University, Durham, NC, USA.
University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, University of Florida, Gainesville, FL, USA.


Mitochondria are key targets of many environmental contaminants, as specific chemicals can interact directly with mitochondrial proteins, lipids, and ribonucleic acids. These direct interactions serve as molecular initiating events (MIEs) that impede ATP 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 (KEs), such as altered membrane potential, mitochondrial fission/fusion, and mtDNA damage, among others. This critical review and analysis reveal current progress on AOPs involving mitochondrial dysfunction and identifies, using a network-based computational approach, the localization of mitochondrial MIEs and KEs within multiple existing AOPs. We also present two case studies: one examining the interaction between mitochondria and immunotoxicity, and a second case study examining the role of early mitochondrial dysfunction in the context of behavior (i.e., locomotor activity). We discuss limitations in current mitochondrial AOPs and highlight opportunities for improving their clarity and detail. Advancing our knowledge regarding KE relationships within the AOP framework will require high-throughput datasets that permit the development and testing of chemical-agnostic AOPs, and high-resolution research that will enhance mechanistic testing and validation of these KE 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, mitochondrial AOPs are expected to play a significant, if not central, role in environmental toxicology. This article is protected by copyright. All rights reserved.


Adverse outcome pathways; High-throughput screening; Immune toxicity; Locomotion; Mitochondria; Weight of evidence


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