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Research Article

Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

Martin Picard, Meagan J. McManus, Jason D. Gray, Carla Nasca, Cynthia Moffat, Piotr K. Kopinski, Erin L. Seifert, Bruce S. McEwen, and Douglas C. Wallace
  1. aCenter for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104;
  2. bDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
  3. cLaboratory for Neuroendocrinology, The Rockefeller University, New York, NY 10065;
  4. dMitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107

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PNAS December 1, 2015 112 (48) E6614-E6623; first published November 16, 2015; https://doi.org/10.1073/pnas.1515733112
Martin Picard
aCenter for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104;
bDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Meagan J. McManus
aCenter for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104;
bDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Jason D. Gray
cLaboratory for Neuroendocrinology, The Rockefeller University, New York, NY 10065;
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Carla Nasca
cLaboratory for Neuroendocrinology, The Rockefeller University, New York, NY 10065;
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Cynthia Moffat
dMitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107
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Piotr K. Kopinski
aCenter for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104;
bDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Erin L. Seifert
dMitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107
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Bruce S. McEwen
cLaboratory for Neuroendocrinology, The Rockefeller University, New York, NY 10065;
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Douglas C. Wallace
aCenter for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104;
bDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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  • For correspondence: wallaced1@email.chop.edu
  1. Contributed by Douglas C. Wallace, September 22, 2015 (sent for review June 16, 2015; reviewed by José Antonio Enríquez and Susan Lutgendorf)

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Significance

In humans and animals, stress triggers multisystemic physiological responses that vary in nature and magnitude. The organism’s response to stress, rather than actual stressors, leads to allostatic load that predisposes to disease. This study in mice demonstrates that a specific cellular component that sustains life via energy transformation and intracellular signaling—the mitochondrion—influences the organism’s integrated response to psychological stress. Each component of the stress response assessed was modified by at least one mitochondrial defect. When analyzed collectively, stress-induced neuroendocrine, inflammatory, metabolic, and transcriptional responses coalesced into unique signatures that distinguish groups based on their mitochondrial genotype. This work shows that mitochondria can regulate complex whole-body physiological responses, impacting stress perception at the cellular and organismal levels.

Abstract

The experience of psychological stress triggers neuroendocrine, inflammatory, metabolic, and transcriptional perturbations that ultimately predispose to disease. However, the subcellular determinants of this integrated, multisystemic stress response have not been defined. Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism’s multisystemic response to psychological stress. By mutating or deleting mitochondrial genes encoded in the mtDNA [NADH dehydrogenase 6 (ND6) and cytochrome c oxidase subunit I (COI)] or nuclear DNA [adenine nucleotide translocator 1 (ANT1) and nicotinamide nucleotide transhydrogenase (NNT)], we selectively impaired mitochondrial respiratory chain function, energy exchange, and mitochondrial redox balance in mice. The resulting impact on physiological reactivity and recovery from restraint stress were then characterized. We show that mitochondrial dysfunctions altered the hypothalamic–pituitary–adrenal axis, sympathetic adrenal–medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stress-response signature. These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key pathophysiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases.

  • stress reactivity
  • mitochondria
  • HPA axis
  • catecholamines
  • hippocampus

Footnotes

  • ↵1Present address: Division of Behavioral Medicine, Department of Psychiatry, Department of Neurology, and Columbia Translational Neuroscience Initiative, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032.

  • ↵2To whom correspondence should be addressed. Email: wallaced1{at}email.chop.edu.
  • Author contributions: M.P., M.J.M., and D.C.W. designed research; M.P., M.J.M., C.M., and E.L.S. performed research; M.P., M.J.M., J.D.G., C.N., C.M., E.L.S., B.S.M., and D.C.W. analyzed data; and M.P., M.J.M., P.K.K., and D.C.W. wrote the paper.

  • Reviewers: J.A.E., Centro Nacional de Investigaciónes Cardiovasculares Carlos III; and S.L., University of Iowa.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1515733112/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Stress response modulation by mitochondria
Martin Picard, Meagan J. McManus, Jason D. Gray, Carla Nasca, Cynthia Moffat, Piotr K. Kopinski, Erin L. Seifert, Bruce S. McEwen, Douglas C. Wallace
Proceedings of the National Academy of Sciences Dec 2015, 112 (48) E6614-E6623; DOI: 10.1073/pnas.1515733112

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Stress response modulation by mitochondria
Martin Picard, Meagan J. McManus, Jason D. Gray, Carla Nasca, Cynthia Moffat, Piotr K. Kopinski, Erin L. Seifert, Bruce S. McEwen, Douglas C. Wallace
Proceedings of the National Academy of Sciences Dec 2015, 112 (48) E6614-E6623; DOI: 10.1073/pnas.1515733112
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