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Mitochondria-Focused Gene Expression Profile Reveals Common OPEN Citation: Transl Psychiatry (2015) 5, e580; doi:10.1038/tp.2015.65 www.nature.com/tp ORIGINAL ARTICLE Mitochondria-focused gene expression profile reveals common pathways and CPT1B dysregulation in both rodent stress model and human subjects with PTSD L Zhang1,3,HLi1,3,XHu1,3, DM Benedek1,3, CS Fullerton1,3, RD Forsten2,3, JA Naifeh1,XLi1,HWu1, KN Benevides1,TLe1, S Smerin1, DW Russell1 and RJ Ursano1,3 Posttraumatic stress disorder (PTSD), a trauma-related mental disorder, is associated with mitochondrial dysfunction in the brain. However, the biologic approach to identifying the mitochondria-focused genes underlying the pathogenesis of PTSD is still in its infancy. Previous research, using a human mitochondria-focused cDNA microarray (hMitChip3) found dysregulated mitochondria- focused genes present in postmortem brains of PTSD patients, indicating that those genes might be PTSD-related biomarkers. To further test this idea, this research examines profiles of mitochondria-focused gene expression in the stressed-rodent model (inescapable tail shock in rats), which shows characteristics of PTSD-like behaviors and also in the blood of subjects with PTSD. This study found that 34 mitochondria-focused genes being upregulated in stressed-rat amygdala. Ten common pathways, including fatty acid metabolism and peroxisome proliferator-activated receptors (PPAR) pathways were dysregulated in the amygdala of the stressed rats. Carnitine palmitoyltransferase 1B (CPT1B), an enzyme in the fatty acid metabolism and PPAR pathways, was significantly over-expressed in the amygdala (Po0.007) and in the blood (Po0.01) of stressed rats compared with non-stressed controls. In human subjects with (n = 28) or without PTSD (n = 31), significant over-expression of CPT1B in PTSD was also observed in the two common dysregulated pathways: fatty acid metabolism (P = 0.0027, false discovery rate (FDR) = 0.043) and PPAR (P = 0.006, FDR = 0.08). Quantitative real-time polymerase chain reaction validated the microarray findings and the CPT1B result. These findings indicate that blood can be used as a specimen in the search for PTSD biomarkers in fatty acid metabolism and PPAR pathways, and, in addition, that CPT1B may contribute to the pathology of PTSD. Translational Psychiatry (2015) 5, e580; doi:10.1038/tp.2015.65; published online 16 June 2015 INTRODUCTION apoptosis and acts as calcium buffer. It is also a source of free 6,7 Posttraumatic stress disorder (PTSD) is a complex mental disorder radicals. The free radicals can damage mitochondrial DNA 8 that can develop in response to a traumatic event (for example, an resulting in the production of more free radicals. Thus, the accident or combat exposure). In the United States, war-related complementary functions of the mitochondria include bioener- PTSD carry a substantial social and financial burden considering getics, amino acid production and cell death. there are approximately 500 000 veterans estimated to suffer from Cumulative evidences from electron microscopy, imaging, gene PTSD; as such, it is not surprising that the disease accounts for expression, genotyping and sequencing studies indicate that there is mitochondrial dysfunction in schizophrenia, bipolar over 20 percent of all U.S. Department of Veterans Affairs disorder, major depressive disorder and PTSD.9,10 Monoamine compensation claims. However, little is known about the under- oxidase A and B enzymes and benzodiazepine receptors, which lying molecular mechanisms of PTSD. Currently, a PTSD diagnosis are the psychopharmacological targets in the membrane of the is established on the basis of clinical history, mental health mitochondria further supports the relationship between the examination using a clinically structured interview and clinician mitochondria and psychiatric disorders.11–13 Therefore, direct 1 fi administered or self-reported symptom checklist. The identi ca- examination of mitochondrial gene expression profiles from tion of biomarkers for risk of PTSD, PTSD presence or PTSD severity animal models and subjects with PTSD may provide further would help in the development of biologically based approaches details of the role of mitochondria in psychiatric disorders in to the assessment and management of the disorder. general, and PTSD in particular, and help identify possible In addition to neurochemical, functional and structural altera- biomarkers for PTSD.4 tions in the neuroendocrine system in patients with such mental Previous research has demonstrated mitochondrial dysfunction disorders, mitochondrial dysfunctions are increasingly recognized in the PTSD brain cortex, indicating that expression fingerprints – as key components in stress-related pathology.2 5 The mitochon- may serve as biomarkers for a PTSD diagnosis.4 This research drion is a membrane-bound organelle present in most eukaryotic found PTSD-specific expression fingerprints of 800 informative cells. It has a role in amino acid, lipid, steroid metabolism and mitochondria-focused genes across all 12 of the postmortem 1Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA and 2U.S. Army Pacific Command, Hawaiian Islands, HI, USA. Correspondence: Dr L Zhang, Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. E-mail: [email protected] 3These authors contributed equally to this work. Received 22 December 2014; revised 9 March 2015; accepted 24 March 2015 Mitochondria-focused gene expression profile and PTSD L Zhang et al 2 brains sampled, and 119 (± 41.25, Po0.05) and 42 ( ± 41.60, response, circadian rhythms, intraneuronal signal transduction and Po0.05) dysregulated genes between the PTSD and control neurotransmitters. The oligonucleotides used were designed with the samples.4 These fingerprints distinguished the PTSD cortices from software MacVector v10.6.0 (MacVector) using full-length messenger RNA controls. The 119 dysregulated genes were associated with (mRNA) sequences as the templates according to published criteria. An fi ′ mitochondrial dysfunction, oxidative phosphorylation, cell survival amino-C6 modi er was added to the 5 end of each oligonucleotide probe to enhance the binding of the DNA to glass slides and the accessibility of apoptosis and neurological diseases. Fifty dysregulated genes hybridization with target DNA. The 1500 test genes (including 80 ‘house- were present in the molecular networks known to be involved in keeping’ genes as positive controls) and 36 negative controls (non-rat neuronal function survival and that contain targets for neuropsy- DNA) were printed, each in triplicates, onto the N-hydroxysuccinimide 14 chiatric drugs. Thirty of these dysregulated mitochondria- ester reactive group-coated glass slides (CodeLink Activated Slide, focused genes are associated with a number of neuropsychiatric SurModics, Eden Prairie, MN, USA). DNA probes in the print buffer disorders. These results are consistent with others showing the (50 mM sodium phosphate), at a final concentration of 20 μM of 5′-amino- relationship between traumatic stress and mitochondrial C6 modified 50-mers, were printed in the Class 100 super-clean dysfunction.2,3 For example, psychological stress and anxious environment, using 100-micron pins and the GeneMachine OmniGrid behavior15 are associated with oxidative stress;16 the enzymes 100 Microarrayer (Genomic Solutions, Ann Arbor, MI, USA). involved in oxidative stress (glyoxalase 1 and glutathione reductase 1) regulate anxiety in mice.15 Chronic stress inhibits Rat RNA purification the activity of mitochondrial respiratory complexes in rats.17 The The amygdalae of rats and whole blood from both the stress (n = 10) and stress hormone cortisol results in the binding of the glucocorticoid control (n = 10) groups were dissected immediately after euthanasia.18 receptor to mitochondrial membranes and regulates apoptosis.2 Total amygdala RNA was purified from rat brain tissues by using a PAXgene In this study, we examined profiles of mitochondria-focused gene RNA Kit (QIAGEN, Valencia, CA, USA) following the manufacturer’s expression in the stressed-rodent model (inescapable tail shock in instructions. rats), using rat mitochondria neuronal chip containing 37 mitochondrial DNA-encoded genes, 1,098 nuclear DNA-encoded Microarray hybridization for rat study and mitochondria-focused genes and 365 genes associated with One microgram of RNA per sample was used for Cy5-dUTP labeling of neuronal functions. The inescapable tail shock rat model has cDNA by use of the expression array detection kit (3DNA Array 900, shown PTSD-like behaviors and also biochemical changes seen Genisphere, Hatfield, PA, USA) following the manufacturer’s instructions. in subjects with PTSD.18,19 Utilizing an identical human Slides were scanned using 5-micron resolution and the LOWESS method mitochondria-focused gene microarray (hMitChip3) approach in with a ScanArray Microarray Scanner (PerkinElmer, Waltham, MA, USA). Triplicate microarray experiments were performed for each RNA sample conjunction with our previous human brain data, we examined fi fi puri ed from the amygdala and human blood. The background-subtracted whether the pro le of stress-induced gene expression in animals mean values of the measured gene expression signal intensities were used was also present in the blood of subjects with PTSD and therefore for microarray data analysis. All microarray experiments were performed in whether
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