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Review Advance Publication

Environ Health Perspect; DOI:10.1289/ehp.1408418

Mitochondria, Energetics, Epigenetics, and Cellular Responses to Stress

Daniel T. Shaughnessy,1 Kimberly McAllister,1 Leroy Worth, 1 Astrid C. Haugen,1 Joel N. Meyer,2 Frederick E. Domann,3 Bennett Van Houten,4 Raul Mostoslavsky,5 Scott J. Bultman,6 Andrea A. Baccarelli,7 Thomas J. Begley,8 Robert Sobol,4,9 Matthew D. Hirschey,10Trey Ideker,11 Janine H. Santos,12 William C. Copeland,13 Raymond R.Tice,14 David M. Balshaw,1 and Frederick L. Tyson
Author Affiliations close
1Division of Extramural Research and Training, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA; 2Nicholas School of the Environment, Duke University, Durham, North Carolina, USA; 3Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; 4University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; 5The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; 6Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; 7Laboratory of Environmental Epigenetics, Exposure Epidemiology and Risk Program, Harvard School of Public Health, Boston, Massachusetts, USA; 8College of Nanoscale Science and Engineering, Albany, New York, USA; 9Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; 10Duke University Medical Center, Durham, North Carolina, USA; 11Departments of Medicine and Bioengineering, University of California San Diego, La Jolla, California, USA; 12Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences NIH, Research Triangle Park, North Carolina, USA; 13Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA; 14Biomolecular Screening Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA
About This Article open

This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. EHP Advance Publication articles are completely citable using the DOI number assigned to the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.

Citation: Shaughnessy DT, McAllister K, Worth L, Haugen AC, Meyer JN, Domann FE, Van Houten B, Mostoslavsky R, Bultman SJ, Baccarelli AA, Begley TJ, Sobol R, Hirschey MD, Ideker T, Santos JH, Copeland WC, Tice RR, Balshaw DM, Tyson FL. Mitochondria, Energetics, Epigenetics, and Cellular Responses to Stress. Environ Health Perspect; http://dx.doi.org/10.1289/ehp.1408418.

Received: 13 March 2014
Accepted: 14 August 2014
Advance Publication: 15 August 2014

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Abstract

Background: Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response (DDR), and epigenetic alterations. Mitochondria play a central role in these pathways, not only through energetics and ATP production but also through metabolites generated in the Tricarboxylic Acid (TCA) cycle, and mitochondria-nuclear signaling related to mitochondria morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation.

Objectives: This review investigates the concept of bidirectional interactions between mitochondria and cellular pathways in response to environmental stress with a focus on epigenetic regulation, and DNA repair and DDR pathways as examples of biological processes that respond to exogenous insults through changes in homeostasis and altered mitochondrial function.

Methods: NIEHS sponsored a workshop on Mitochondria, Energetics, Epigenetics, Environment and DNA Damage Response on March 25-26, 2013. Key points and ideas emerging from this meeting are summarized.

Discussion: A more comprehensive understanding of signaling mechanisms (cross-talk) between the mitochondria and nucleus is central to elucidating the integration of mitochondrial functions with other cellular response pathways in modulating the effects of environmental agents. Recent studies have highlighted the importance of mitochondrial functions in epigenetic regulation and DDR with environmental stress. Development and application of novel technologies, enhanced experimental models, and a systems-type research approach will help to discern how environmentally induced mitochondrial dysfunction affects key mechanistic pathways.

Conclusions: Understanding mitochondrial-cell signaling will provide insight into individual responses to environmental hazards, improving prediction of hazard and susceptibility to environmental stressors.


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