Mitochondrial DNA copy number is reduced in male combat veterans with PTSD

Bersani, Francesco Saverio; Morley, Claire; Lindqvist, Daniel; Epel, Elissa S.; Picard, Martin; Yehuda, Rachel; Flory, Janine D.; Bierer, Linda M.; Makotkine, Iouri; Abu‐Amara, Duna; Coy, Michelle; Reus, Victor I.; Lin, Jue; Blackburn, Elizabeth H.; Marmar, Charles R.; Wolkowitz, Owen M.; Mellon, Synthia H.

doi:10.1016/j.pnpbp.2015.06.012

Cited by 77 publications

(56 citation statements)

References 79 publications

(90 reference statements)

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“…Multiple physiological systems at the neuronal, metabolic, inflammatory, genomic and epigenomic levels are known to be affected in PTSD 2 , 3 . Previous studies from our PTSD Systems Biology consortium reported associations between PTSD and insulin resistance 4 , inflammation 5 , reduced mitochondrial copy number 6 , and lower methylation of the glucocorticoid receptor (NR3C1) gene 7 in the same cohorts assessed in the present study. The data from animal models and humans with PTSD reveal association between inflammation and metabolic syndrome 8 .…”

supporting

confidence: 65%

Mechanistic insights on metabolic dysfunction in PTSD: Role of glucocorticoid receptor sensitivity and energy deficit

Somvanshi

Mellon

Flory

et al. 2018

Preprint

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PTSD is associated with metabolic comorbidities; however it is not clear how the neuroendocrine disturbances affect metabolism. To analyze this we employed a systems biological approach using an integrated mathematical model of metabolism, HPA axis and inflammation. We combined the metabolomics, neuroendocrine, clinical lab and cytokine data from combat-exposed veterans with and without PTSD, to characterize the differences in regulatory effects. We used the pattern of fold change in metabolites representing pathway level differences as reference for metabolic control analysis (MCA) using the model. MCA revealed parameters constituting the HPA axis, inflammation and GPCR pathway that yielded metabolic dysfunction consistent with PTSD. To support this, we performed causal analysis between regulatory components and the significantly different metabolites in our sample. Causal inference revealed that the changes in glucocorticoid receptor sensitivity were mechanistically associated with metabolic dysfunction and the effects were jointly mediated by insulin resistance, inflammation, oxidative stress and energy deficit.Post-traumatic stress disorder (PTSD) is defined by a complex set of criteria including intrusive reminders, fear memories, emotional distress, hypervigilance and exaggerated startle responses that develop and persist after an exposure to trauma 1 . Multiple physiological systems at the neuronal, metabolic, inflammatory, genomic and epigenomic levels are known to be affected in PTSD 2,3 . Previous studies from our PTSD Systems Biology consortium reported associations between PTSD and insulin resistance 4 , inflammation 5 , reduced mitochondrial copy number 6 , and lower methylation of the glucocorticoid receptor (NR3C1) gene 7 in the same cohorts assessed in the present study. The data from animal models and humans with PTSD reveal association between inflammation and metabolic syndrome 8 . Analysis of metabolomics have revealed metabolic changes consistent with dysregulation in mitochondrial functioning in PTSD 9 . Another study reported differences in the mitochondrial DNA (SNPs) located in NADH dehydrogenase and ATP synthase genes in PTSD 10 . Variants of mitochondrial genes and dysregulation of their associated networks have been reported in the postmortem brains of patients with PTSD 11 .One of the major physiological regulatory axes, Hypothalamic-Pituitary-Adrenal (HPA) axis is implicated in the pathogenesis of PTSD and associated metabolic disorders 12,13 . The HPA axis relays stress signals from the brain to peripheral parts through the release of glucocorticoids (GCs) and catecholamine hormones. GCs orchestrate the activities of several physiological functions through glucocorticoid receptor (GRs) signaling. Therefore, the feedback sensitivity of GC signaling among other factors can influence downstream effects of stress exposure. GR signaling is regulated at transcriptional and epigenetic levels and is dysregulated in HPA axis associated disorders 14 . Recent studies have highlighted the asso...

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supporting

confidence: 65%

Mechanistic insights on metabolic dysfunction in PTSD: Role of glucocorticoid receptor sensitivity and energy deficit

Somvanshi

Mellon

Flory

et al. 2018

Preprint

Self Cite

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“…A few psychiatric studies have examined intracellular mtDNA-cn (primarily in leukocytes) with conflicting results. Reduced mtDNAcn has been reported in post-traumatic stress disorder 47 and in relation to depressive symptoms among elderly communitydwelling women without MDD. 48,49 Higher leukocyte mtDNA-cn has been reported in autism 50 and lifetime psychopathology in healthy people.…”

Section: Discussionmentioning

confidence: 95%

Stress: A deadly weapon

Peñagarikano

2016

Sci. Transl. Med.

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Preclinical data suggest that chronic stress may cause cellular damage and mitochondrial dysfunction, potentially leading to the release of mitochondrial DNA (mtDNA) into the bloodstream. Major depressive disorder has been associated with an increased amount of mtDNA in leukocytes from saliva samples and blood; however, no previous studies have measured plasma levels of free-circulating mtDNA in a clinical psychiatric sample. In this study, free circulating mtDNA was quantified in plasma samples from 37 suicide attempters, who had undergone a dexamethasone suppression test (DST), and 37 healthy controls. We hypothesized that free circulating mtDNA would be elevated in the suicide attempters and would be associated with hypothalamic-pituitaryadrenal (HPA)-axis hyperactivity. Suicide attempters had significantly higher plasma levels of free-circulating mtDNA compared with healthy controls at different time points (pre-and post-DST; all P-values o2.98E − 12, Cohen's d ranging from 2.55 to 4.01). Pre-DST plasma levels of mtDNA were positively correlated with post-DST cortisol levels (rho = 0.49, P o 0.003). Suicide attempters may have elevated plasma levels of free-circulating mtDNA, which are related to impaired HPA-axis negative feedback. This peripheral index is consistent with an increased cellular or mitochondrial damage. The specific cells and tissues contributing to plasma levels of free-circulating mtDNA are not known, as is the specificity of this finding for suicide attempters. Future studies are needed in order to better understand the relevance of increased free-circulating mtDNA in relation to the pathophysiology underlying suicidal behavior and depression.

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“…Mitochondrial content in granulocytes from male combat veterans with post‐traumatic stress disorder (PTSD) has also been found to be decreased (Bersani et al . ). While cortisol was not measured in the PTSD study, cortisol levels are known to be dysregulated in individuals with PTSD (Wichmann et al .…”

Section: Discussionmentioning

confidence: 97%

“…Maternal glucocorticoids have been shown to reduce mitochondrial content in fetal heart tissues (Richards et al 2014), and in vitro studies have demonstrated decreased mitochondrial content in endothelial cells exposed to glucocorticoids (Gero & Szabo, 2016). Mitochondrial content in granulocytes from male combat veterans with post-traumatic stress disorder (PTSD) has also been found to be decreased (Bersani et al 2016). While cortisol was not measured in the PTSD study, cortisol levels are known to be dysregulated in individuals with PTSD (Wichmann et al 2017), and may have contributed to the decreased mitochondrial content in the study.…”

Section: Effects Of Corticosterone On Mitochondrial Functionmentioning

confidence: 99%

Maternal corticosterone in the mouse alters oxidative stress markers, antioxidant function and mitochondrial content in placentas of female fetuses

Bartho

Holland

Moritz

et al. 2019

The Journal of Physiology

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Key points Maternal exposure to the stress hormone corticosterone is known to programme a range of sex specific disease outcomes in offspring. Sex differences in placental adaptations are thought to mediate these processes. Placental oxidative stress is implicated in a range of pregnancy disorders but the role of placental oxidative stress in sex specific disease outcomes following prenatal corticosterone exposure is unknown. This study demonstrates that maternal corticosterone reduced placental hydrogen peroxide and 8‐hydroxy‐2′‐deoxyguanosine concentrations but increased protein carbonyl content and advanced glycation end product concentrations in placentas of female fetuses but not male fetuses. These results highlight that placentas of female fetuses respond differently to maternal corticosterone exposure, with oxidative stress a major finding in placentas of female fetuses. Abstract Maternal exposure to glucocorticoids during pregnancy increases offspring risk of developing a range of sex specific disease phenotypes. These sex specific disease outcomes are thought to be in part mediated by different placental adaptations in males and females. The placenta is a highly metabolic organ which is vulnerable to the effects of oxidative stress. In other tissues, males and females have been shown to respond differently to the pro‐oxidant effects of glucocorticoids. This study therefore used a well characterized animal model of maternal corticosterone exposure to investigate sex specific alterations in reactive oxygen species production, antioxidant concentrations and mitochondrial properties that might contribute to sex differences in placental outcomes. C57BL/6 mice were implanted with osmotic minipumps containing corticosterone (33 μg kg−1 h−1) at embryonic day (E) 12.5 and placentas collected at E14.5 for analysis. Corticosterone exposure reduced placental hydrogen peroxide (H2O2) and 8‐hydroxy‐2′‐deoxyguanosine concentrations but increased protein carbonyl content and advanced glycation end product concentrations in placentas of female fetuses but not male fetuses. This dysregulation of different markers of oxidative stress may be due to increased placental activity of thioredoxin reductase in female but not male fetuses. Corticosterone reduced placental mitochondrial content but increased protein expression of the autophagosome cargo protein p62. This study demonstrates that placentas of female fetuses respond differently to maternal corticosterone exposure and highlights an important role of reactive oxygen species, mitochondrial adaptations and antioxidant responses in glucocorticoid induced programmed disease.

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Mitochondrial DNA copy number is reduced in male combat veterans with PTSD

Cited by 77 publications

References 79 publications

Mechanistic insights on metabolic dysfunction in PTSD: Role of glucocorticoid receptor sensitivity and energy deficit

Mechanistic insights on metabolic dysfunction in PTSD: Role of glucocorticoid receptor sensitivity and energy deficit

Stress: A deadly weapon

Maternal corticosterone in the mouse alters oxidative stress markers, antioxidant function and mitochondrial content in placentas of female fetuses

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