title: Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress.
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.
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Martin
authors.initials: M
authors.lastname: Picard
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Meagan J
authors.initials: MJ
authors.lastname: McManus
authors.affiliation: Laboratory for Neuroendocrinology, The Rockefeller University, New York, NY 10065;
authors.forename: Jason D
authors.initials: JD
authors.lastname: Gray
authors.affiliation: Laboratory for Neuroendocrinology, The Rockefeller University, New York, NY 10065;
authors.forename: Carla
authors.initials: C
authors.lastname: Nasca
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Moffat
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Piotr K
authors.initials: PK
authors.lastname: Kopinski
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Seifert
authors.affiliation: Laboratory for Neuroendocrinology, The Rockefeller University, New York, NY 10065;
authors.forename: Bruce S
authors.initials: BS
authors.lastname: McEwen
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104; wallaced1@email.chop.edu.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics; D000324:Adrenocorticotropic Hormone / Q000097:blood; D052636:Allostasis; D000818:Animals; D002395:Catecholamines / Q000097:blood; D004272:DNA, Mitochondrial / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics; D005786:Gene Expression Regulation; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000473:pathology*; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics; D061087:NADP Transhydrogenase, AB-Specific / Q000235:genetics; D018384:Oxidative Stress; D015398:Signal Transduction; D013315:Stress, Psychological; D014158:Transcription, Genetic
chemical_list: D033741:Adenine Nucleotide Translocator 1; D002395:Catecholamines; D004272:DNA, Mitochondrial; D015850:Interleukin-6; D024101:Mitochondrial Proteins; C577686:interleukin-6, mouse; D000324:Adrenocorticotropic Hormone; D061087:NADP Transhydrogenase, AB-Specific; C556048:Nnt protein, mouse; D009245:NADH Dehydrogenase; C508029:NADH dehydrogenase subunit 6, mouse; D003576:Electron Transport Complex IV
keywords: HPA axis; catecholamines; hippocampus; mitochondria; stress reactivity