Mitochondria as a Target of Environmental Toxicants

toxicological sciences 134(1), 1–17 2013 doi:10.1093/toxsci/kft102 Advance Access publication April 29, 2013 Review Mitochondria as a Target of Environmental Toxicants Joel N. Meyer,*,1 Maxwell C. K. Leung,* John P. Rooney,* Ataman Sendoel,† Michael O. Hengartner,† Glen E. Kisby,‡ and Amanda S. Bess* *Nicholas School of the Environment, Duke University, Durham, North Carolina; †Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland; and ‡Department of Basic Medical Sciences, Western University of Health Sciences, Lebanon, Oregon To whom correspondence should be addressed at Nicholas School of the Environment, Duke University, Box 90328, A354 LSRC, Research Dr, Durham, NC 27708-0328. Fax: (919) 668-1799. E-mail: . 1 Received January 23, 2013; accepted April 23, 2013 Enormous strides have recently been made in our understanding of the biology and pathobiology of mitochondria. Many diseases have been identified as caused by mitochondrial dysfunction, and many pharmaceuticals have been identified as previously unrecognized mitochondrial toxicants. A much smaller but growing literature indicates that mitochondria are also targeted by environmental pollutants. We briefly review the importance of mitochondrial function and maintenance for health based on the genetics of mitochondrial diseases and the toxicities resulting from pharmaceutical exposure. We then discuss how the principles of mitochondrial vulnerability illustrated by those fields might apply to environmental contaminants, with particular attention to factors that may modulate vulnerability including genetic differences, epigenetic interactions, tissue characteristics, and developmental stage. Finally, we review the literature related to environmental mitochondrial toxicants, with a particular focus on those toxicants that target mitochondrial DNA. We conclude that the fields of environmental toxicology and environmental health should focus more strongly on mitochondria. Key Words: contaminants; mitochondria; mitochondrial DNA; mitochondrial toxicity; mitochondrial disease. Mitochondria and Mitochondrial DNA Mitochondria are essential organelles best known for ATP generation and their involvement in apoptosis. They also play critical roles in other key processes including calcium, copper, and iron homeostasis; heme and iron-sulfur cluster assembly; synthesis of pyrimidines and steroids; thermogenesis and fever response; and calcium signaling. The great majority of the ~1000–1500 (Calvo and Mootha, 2010) proteins that carry out these functions are imported from the cytoplasm via mitochondria targeting sequences or other mechanisms (Bolender et al., 2008), and the proteins present vary significantly with tissue (Johnson et al., 2007). This variability probably reflects extensive variability in function, ranging from energy production in muscle mitochondria to steroid synthesis in adrenal mitochondria (Vafai and Mootha, 2012). A small number (13 in humans) is encoded in the mitochondrial genome, along with the tRNA and rRNAs required for their synthesis. These proteins are components of complexes I, III, IV, and V of the electron transport chain (ETC). Despite their small number, they are essential and are transcribed at high rates: mtRNA represents ~5% of total cellular RNA in many tissues but as high as 30% in heart cells (Mercer et al., 2011). Mitochondrial morphology also varies with cell type, developmental stage, and environment (Jansen and de Boer, 1998; Rube and van der Bliek, 2004; Vafai and Mootha, 2012) (Fig. 1). Morphology ranges from highly fragmented to highly networked, is regulated via the processes of mitochondrial fusion and fission, and is responsive to a variety of stressors (Jendrach et al., 2008; Twig and Shirihai, 2011). Morphological dynamics are critical for maintenance of mitochondrial function (Green and Van Houten, 2011; Youle and van der Bliek, 2012). The amount of cellular mitochondria and their content are regulated via mitochondrial biogenesis, nuclear signaling–mediated nuclear and mitochondrial transcription, autophagy, and intraorganellar degradation processes (Diaz and Moraes, 2008; Mijaljica et al., 2007; Piantadosi and Suliman, 2012; Scarpulla, 2008). “Mitophagy” can selectively remove damaged mitochondria (Kim and Lemasters, 2011; Kim et al., 2007), and damaged cellular components can be degraded inside the mitochondria or exported to lysosomes and peroxisomes via mitochondriaderived vesicles (Fischer et al., 2012; Nunnari and Suomalainen, 2012). Mitochondria do not merely receive instructions from the nucleus, however, but rather can initiate signaling in a variety of ways. These include “retrograde signaling” (i.e., from the mitochondria to the nucleus; Chae et al., 2013; Liu and Butow, © The Author 2013. Published by Oxford University Press on behalf of the Society of Toxicology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact . 2 MEYER ET AL. Fig. 1. Mitochondrial morphology. Panel (A) shows the mitochondrial network (MitoTracker Red-stained) containing many mtDNA nucleoids (PicoGreenstained) surrounding the nucleus (Hoescht-stained) of a human primary fibroblast (photo: Amanda Bess). Panels (B) and (C) show a transgenic strain of C. elegans that expresses a mitochondrial matrix-targeted green fluorescent protein in body wall muscle cells. The image in panel (B) is from a control nematode, and the image in panel (C) is from a nematode exposed to 1µM carbonyl cyanide m-chlorophenyl hydrazone, a potent ionophore and inhibitor of oxidative phosphorylation that leads to mitochondrial fragmentation; the mitochondrial matrix was visualized via expression of green fluorescent protein (photo: John Rooney). 2006) to coordinate nuclear transcription with mitochondrial needs via pathways including AMP-activated protein kinase, sirtuins, calcium signaling, peroxisome proliferator–activated receptor g coactivator 1a protein, and others (Piantadosi and Suliman, 2012); mitochondrial-nuclear reactive oxygen species (ROS)–mediated signaling (Storz, 2006); cell cycle arrest signaling that may involve proteins with similar functions in the nucleus (Green et al., 2011; Koczor et al., 2009; Kulawiec et al., 2009); and initiation of apoptosis (Tann et al., 2011; Raimundo et al., 2012), as opposed to the better-known amplification of an apoptotic process initiated elsewhere. There is evidence for a “mitocheckpoint” that senses mitochondrial dysfunction and triggers cell cycle arrest (Singh, 2006) although the mechanism for this response is not fully understood. Mitochondrial DNA (mtDNA) in many animal species is a circular intron-free genome consisting of 14,000–17,000 base pa (...truncated)