Mitochondria, Energetics, Epigenetics, and Cellular Responses to Stress

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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 cycle, as well as mitochondria–nuclear signaling related to mitochondria morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation.

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

Methods: The National Institute of Environmental Health Sciences sponsored the Workshop on Mitochondria, Energetics, Epigenetics, Environment, and DNA Damage Response on 25–26 March 2013. Here, we summarize key points and ideas emerging from this meeting.

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 mitochondria–cell signaling will provide insight into individual responses to environmental hazards, improving prediction of hazard and susceptibility to environmental stressors.

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 RW, Hirschey MD, Ideker T, Santos JH, Copeland WC, Tice RR, Balshaw DM, Tyson FL. 2014. Mitochondria, energetics, epigenetics, and cellular responses to stress. Environ Health Perspect 122:1271–1278; http://dx.doi.org/10.1289/ehp.1408418

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The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon.

Dallas R Donohoe, Nikhil Garge, Xinxin Zhang … (2011)

The microbiome is being characterized by large-scale sequencing efforts, yet it is not known whether it regulates host metabolism in a general versus tissue-specific manner or which bacterial metabolites are important. Here, we demonstrate that microbiota have a strong effect on energy homeostasis in the colon compared to other tissues. This tissue specificity is due to colonocytes utilizing bacterially produced butyrate as their primary energy source. Colonocytes from germfree mice are in an energy-deprived state and exhibit decreased expression of enzymes that catalyze key steps in intermediary metabolism including the TCA cycle. Consequently, there is a marked decrease in NADH/NAD(+), oxidative phosphorylation, and ATP levels, which results in AMPK activation, p27(kip1) phosphorylation, and autophagy. When butyrate is added to germfree colonocytes, it rescues their deficit in mitochondrial respiration and prevents them from undergoing autophagy. The mechanism is due to butyrate acting as an energy source rather than as an HDAC inhibitor. Copyright © 2011 Elsevier Inc. All rights reserved.

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Mitochondrial dynamics and apoptosis.

Der-Fen Suen, Kristi Norris, Richard Youle (2008)

In healthy cells, mitochondria continually divide and fuse to form a dynamic interconnecting network. The molecular machinery that mediates this organelle fission and fusion is necessary to maintain mitochondrial integrity, perhaps by facilitating DNA or protein quality control. This network disintegrates during apoptosis at the time of cytochrome c release and prior to caspase activation, yielding more numerous and smaller mitochondria. Recent work shows that proteins involved in mitochondrial fission and fusion also actively participate in apoptosis induction. This review will cover the recent advances and presents competing models on how the mitochondrial fission and fusion machinery may intersect apoptosis pathways.

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Adipose tissue and adipocytes support tumorigenesis and metastasis.

Kristin M Nieman, Iris L. Romero, Bennett Van Houten … (2013)

Adipose tissue influences tumor development in two major ways. First, obese individuals have a higher risk of developing certain cancers (endometrial, esophageal, and renal cell cancer). However, the risk of developing other cancers (melanoma, rectal, and ovarian) is not altered by body mass. In obesity, hypertrophied adipose tissue depots are characterized by a state of low grade inflammation. In this activated state, adipocytes and inflammatory cells secrete adipokines and cytokines which are known to promote tumor development. In addition, the adipocyte mediated conversion of androgens to estrogen specifically contributes to the development of endometrial cancer, which shows the greatest relative risk (6.3-fold) increase between lean and obese individuals. Second, many tumor types (gastric, breast, colon, renal, and ovarian) grow in the anatomical vicinity of adipose tissue. During their interaction with cancer cells, adipocytes dedifferentiate into pre-adipocytes or are reprogrammed into cancer-associated adipocytes (CAA). CAA secrete adipokines which stimulate the adhesion, migration, and invasion of tumor cells. Cancer cells and CAA also engage in a dynamic exchange of metabolites. Specifically, CAA release fatty acids through lipolysis which are then transferred to cancer cells and used for energy production through β-oxidation. The abundant availability of lipids from adipocytes in the tumor microenvironment, supports tumor progression and uncontrolled growth. Given that adipocytes are a major source of adipokines and energy for the cancer cell, understanding the mechanisms of metabolic symbiosis between cancer cells and adipocytes, should reveal new therapeutic possibilities. This article is part of a Special Issue entitled Lipid Metabolism in Cancer. Copyright © 2013 Elsevier B.V. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Environ Health Perspect

Journal ID (iso-abbrev): Environ. Health Perspect

Journal ID (publisher-id): EHP

Title: Environmental Health Perspectives

Publisher: NLM-Export

ISSN (Print): 0091-6765

ISSN (Electronic): 1552-9924

Publication date (Electronic): 15 August 2014

Publication date (Print): December 2014

Volume: 122

Issue: 12

Pages: 1271-1278

Affiliations

[1 ]Division of Extramural Research and Training, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina, USA

[2 ]Nicholas School of the Environment, Duke University, Durham, North Carolina, USA

[3 ]Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA

[4 ]University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

[5 ]Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA

[6 ]Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

[7 ]Laboratory of Environmental Epigenetics, Exposure Epidemiology and Risk Program, Harvard School of Public Health, Boston, Massachusetts, USA

[8 ]SUNY College of Nanoscale Science and Engineering, Albany, New York, USA

[9 ]Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

[10 ]Duke University Medical Center, Durham, North Carolina, USA

[11 ]Department of Medicine, and

[12 ]Department of Bioengineering, University of California San Diego, La Jolla, California, USA

[13 ]Laboratory of Molecular Carcinogenesis, and

[14 ]Laboratory of Molecular Genetics, NIEHS, NIH, DHHS, Research Triangle Park, North Carolina, USA

[15 ]Biomolecular Screening Branch, Division of the National Toxicology Program, NIEHS, NIH, DHHS, Research Triangle Park, North Carolina, USA

Author notes

Address correspondence to D.T. Shaughnessy, Division of Extramural Research and Training, NIEHS, MD K3-12, P.O. Box 12233, Research Triangle Park, NC 27709 USA. Telephone: (919) 541-2506. E-mail: shaughn1@ 123456niehs.nih.gov

Article

Publisher ID: ehp.1408418

DOI: 10.1289/ehp.1408418

PMC ID: 4256704

PubMed ID: 25127496

SO-VID: c5a3aa1c-d389-46bd-9c79-e3858c7174d4

License:

Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, “Reproduced with permission from Environmental Health Perspectives”); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.

History

Date received : 13 March 2014

Date accepted : 14 August 2014

Date: 15 August 2014

Date: 01 December 2014

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Most cited references 74

The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon.

Mitochondrial dynamics and apoptosis.

Adipose tissue and adipocytes support tumorigenesis and metastasis.

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