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Strecker K, Sim EJ, Woike K, Schönfeldt-Lecuona C, Radermacher P, Karabatsiakis A, Kiefer M. Association of the Biopsychosocial Factors Adverse Childhood Experiences, Adult Attachment Style, Emotion Regulation, and Mitochondrial Density in Immune Cells with Major Depressive Disorder. Neuroimmunomodulation 2025; 32:110-123. [PMID: 40159392 DOI: 10.1159/000544833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 02/14/2025] [Indexed: 04/02/2025] Open
Abstract
INTRODUCTION Major depressive disorder (MDD) is one of the most prevalent mental disorders associated with various negative impacts such as lower overall quality of life, increased morbidity risk, and even premature mortality. According to the biopsychosocial model of health and disease, multiple factors contribute to the development and manifestation of MDD. Here, we assessed preselected social, psychological, and biological variables and tested their power to predict MDD diagnosis using logistic regression models. METHODS In 24 patients with current MDD diagnosis and 35 healthy control participants, the following variables were measured to test for associations with MDD diagnosis: (1) emotional neglect and adult attachment style as social variables, (2) thought suppression and cognitive reappraisal as psychological variables, and (3) mitochondrial density (citrate synthase activity as a surrogate marker of mitochondrial density) measured in peripheral blood mononuclear cells (PBMCs) as a biological variable. RESULTS The following biopsychosocial variables were associated with MDD diagnosis. Participants with greater emotional neglect (OR: 1.273, 95% CI: 1.059-1.645), higher levels of intrusive thoughts (OR: 1.738, 95% CI: 1.282-3.066), and decreased mitochondrial density in PBMCs (OR: 0.298, 95% CI: 0.083-0.784) had a higher probability of belonging to the MDD group. CONCLUSIONS In line with biopsychosocial models of depression, the present results indicate that variables at different levels of analysis are conjointly related to MDD. These findings open new perspectives for the diagnosis and treatment of MDD, but they need to be replicated in larger samples in the future.
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Affiliation(s)
- Katharina Strecker
- Department of Psychiatry and Psychotherapy III, Ulm University Clinic, Ulm, Germany
| | - Eun-Jin Sim
- Department of Psychiatry and Psychotherapy III, Ulm University Clinic, Ulm, Germany,
| | - Kathrin Woike
- Department of Psychiatry and Psychotherapy III, Ulm University Clinic, Ulm, Germany
| | | | - Peter Radermacher
- Institute of Anaesthesiological Pathophysiology and Process Development, Ulm University, Ulm, Germany
| | - Alexander Karabatsiakis
- Department of Psychology, Clinical Psychology II, University of Innsbruck, Innsbruck, Austria
| | - Markus Kiefer
- Department of Psychiatry and Psychotherapy III, Ulm University Clinic, Ulm, Germany
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Lejri I, Grimm A, Trempat P, Boujedaini N, Eckert A. Gelsemium low doses protect against serum deprivation-induced stress on mitochondria in neuronal cells. JOURNAL OF ETHNOPHARMACOLOGY 2025; 336:118714. [PMID: 39181289 DOI: 10.1016/j.jep.2024.118714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 08/15/2024] [Accepted: 08/18/2024] [Indexed: 08/27/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Gelsemium dynamized dilutions (GDD) are known as a remedy for a wide range of behavioral and psychological symptoms of depression and anxiety at ultra-low doses, yet the underlying mechanisms of the mode of action of G. sempervirens itself are not well understood. AIM OF THE STUDY The present study was designed to examine the neuroprotective effects of Gelsemium preparations in counteracting stress-related mitochondrial dysfunctions in neuronal cells. MATERIALS AND METHODS We started by studying how serum deprivation affects the mitochondrial functions of human neuroblastoma (SH-SY5Y) cells. Next, we looked into the potential of various Gelsemium dilutions to improve cell survival and ATP levels. After identifying the most effective dilutions, 3C and 5C, we tested their ability to protect SH-SY5Y cells from stress-induced mitochondrial deficits. We measured total and mitochondrial superoxide anion radicals using fluorescent dyes dihydroethidium (DHE) and the red mitochondrial superoxide indicator (MitoSOX). Additionally, we assessed total nitric oxide levels with 4,5-diaminofluorescein diacetate (DAF-2DA), examined the redox state using pRA305 cells stably transfected with a plasmid encoding a redox-sensitive green fluorescent protein, and analyzed mitochondrial network morphology using an automated high-content analysis device, Cytation3. Furthermore, we investigated bioenergetics by measuring ATP production with a bioluminescence assay (ViaLighTM HT) and evaluated mitochondrial respiration (OCR) and glycolysis (ECAR) using the Seahorse Bioscience XF24 Analyzer. Finally, we determined cell survival using an MTT reduction assay. RESULTS Our research indicates that Gelsemium dilutions (3C and 5C) exhibited neuroprotective effects by: - Normalizing total and mitochondrial superoxide anion radicals and total nitric oxide levels. - Regulating the mitochondrial redox environment and mitochondrial networks morphology. - Increasing ATP generation as well as OCR and ECAR levels, thereby reducing the viability loss induced by serum withdrawal stress. CONCLUSIONS These findings highlight that dynamized Gelsemium preparations may have neuroprotective effects against stress-induced cellular changes in the brain by regulating mitochondrial functions, essential for the survival, plasticity, and function of neurons in depression.
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Affiliation(s)
- Imane Lejri
- Research Cluster Molecular & Cognitive Neuroscience, Neurobiology Laboratory for Brain Aging and Mental Health, University of Basel, Basel, Switzerland; Psychiatric University Clinics, Basel, Switzerland.
| | - Amandine Grimm
- Research Cluster Molecular & Cognitive Neuroscience, Neurobiology Laboratory for Brain Aging and Mental Health, University of Basel, Basel, Switzerland; Psychiatric University Clinics, Basel, Switzerland.
| | | | | | - Anne Eckert
- Research Cluster Molecular & Cognitive Neuroscience, Neurobiology Laboratory for Brain Aging and Mental Health, University of Basel, Basel, Switzerland; Psychiatric University Clinics, Basel, Switzerland.
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Sánchez-Badajos S, Ortega-Vázquez A, López-López M, Monroy-Jaramillo N. Valproic Acid and Lamotrigine Differentially Modulate the Telomere Length in Epilepsy Patients. J Clin Med 2025; 14:255. [PMID: 39797337 PMCID: PMC11720991 DOI: 10.3390/jcm14010255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 12/30/2024] [Accepted: 01/02/2025] [Indexed: 01/13/2025] Open
Abstract
Background/Objectives: Antiseizure drugs (ASDs) are the primary therapy for epilepsy, and the choice varies according to seizure type. Epilepsy patients experience chronic mitochondrial oxidative stress and increased levels of pro-inflammatory mediators, recognizable hallmarks of biological aging; however, few studies have explored aging markers in epilepsy. Herein, we addressed for the first time the impact of ASDs on molecular aging by measuring the telomere length (TL) and mtDNA copy number (mtDNA-CN). Methods: We used real-time quantitative PCR (QPCR) in epilepsy patients compared to matched healthy controls (CTs) and assessed the association with plasma levels of ASDs and other clinical variables. The sample comprised 64 epilepsy patients and 64 CTs. Patients were grouped based on monotherapy with lamotrigine (LTG) or valproic acid (VPA), and those treated with a combination therapy (LTG + VPA). Multivariable logistic regression was applied to analyze the obtained data. Results: mtDNA-CN was similar between patients and controls, and none of the comparisons were significant for this marker. TL was shorter in not seizure-free patients than in CTs (1.50 ± 0.35 vs. 1.68 ± 0.34; p < 0.05), regardless of the ASD therapy. These patients exhibited the highest proportion of adverse drug reactions. TL was longer in patients on VPA monotherapy, followed by patients on LTG monotherapy and patients on an LTG + VPA combined scheme (1.77 ± 0.24; 1.50 ± 0.32; 1.36 ± 0.37, respectively; p < 0.05), suggesting that ASD treatment differentially modulates TL. Conclusions: Our findings suggest that clinicians could consider TL measurements to decide the best ASD treatment option (VPA and/or LTG) to help predict ASD responses in epilepsy patients.
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Affiliation(s)
- Salvador Sánchez-Badajos
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Mexico City 04960, Mexico;
| | - Alberto Ortega-Vázquez
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, Mexico City 04960, Mexico; (A.O.-V.); (M.L.-L.)
| | - Marisol López-López
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, Mexico City 04960, Mexico; (A.O.-V.); (M.L.-L.)
| | - Nancy Monroy-Jaramillo
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez (INNNMVS), Mexico City 14269, Mexico
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Jing P, Yu HH, Wu TT, Yu BH, Liang M, Xia TT, Xu XW, Xu T, Liu LJ, Zhang XB. Major depressive disorder is associated with mitochondrial ND6 T14502C mutation in two Han Chinese families. World J Psychiatry 2024; 14:1746-1754. [PMID: 39564165 PMCID: PMC11572673 DOI: 10.5498/wjp.v14.i11.1746] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 09/06/2024] [Accepted: 10/28/2024] [Indexed: 11/07/2024] Open
Abstract
BACKGROUND Globally, the World Health Organization ranks major depressive disorder (MDD) as the leading cause of disability. However, MDD molecular etiology is still poorly understood. AIM To explore the possible association between mitochondrial ND6 T14502C mutation and MDD. METHODS Clinical data were collected from two pedigrees, and detailed mitochondrial genomes were obtained for the two proband members. The assessment of the resulting variants included an evaluation of their evolutionary conservation, allelic frequencies, as well as their structural and functional consequences. Detailed mitochondrial whole genome analysis, phylogenetic, and haplotype analysis were performed on the probands. RESULTS Herein, we reported the clinical, genetic, and molecular profiling of two Chinese families afflicted with MDD. These Chinese families exhibited not only a range of onset and severity ages in their depression but also extremely low penetrances to MDD. Sequence analyses of mitochondrial genomes from these pedigrees have resulted in the identification of a homoplasmic T14502C (I58V) mutation. The polymorphism is located at a highly conserved isoleucine at position 58 of ND6 and distinct mitochondrial DNA (mtDNA) polymorphisms originating from haplogroups M10 and H2. CONCLUSION Identifying the T14502C mutation in two individuals with no genetic relation who exhibit symptoms of depression provides compelling evidence that this mutation may be implicated in MDD development. Nonetheless, the two Chinese pedigrees that carried the T14502C mutation did not exhibit any functionally significant mutations in their mtDNA. Therefore, the phenotypic expression of the T14502C mutation related to MDD may be influenced by the nuclear modifier gene(s) or environmental factors.
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Affiliation(s)
- Pan Jing
- Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu Province, China
- Department of Psychiatry, Affiliated Kangning Hospital of Ningbo University, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Hai-Hang Yu
- Department of Psychiatry, Affiliated Kangning Hospital of Ningbo University, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Ting-Ting Wu
- Department of Psychiatry, Affiliated Kangning Hospital of Ningbo University, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Bi-Hua Yu
- Department of Psychiatry, Affiliated Kangning Hospital of Ningbo University, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Ming Liang
- Department of Psychiatry, Xiangshan Third People’s Hospital, Ningbo 315700, Zhejiang Province, China
| | - Ting-Ting Xia
- Department of Psychiatry, Xiangshan Third People’s Hospital, Ningbo 315700, Zhejiang Province, China
| | - Xue-Wen Xu
- Department of Psychiatry, Affiliated Kangning Hospital of Ningbo University, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Ting Xu
- Department of Psychiatry, Affiliated Kangning Hospital of Ningbo University, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Ling-Jiang Liu
- Department of Psychiatry, Affiliated Kangning Hospital of Ningbo University, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Xiao-Bin Zhang
- Department of Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou 215137, Jiangsu Province, China
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Moschonis G, Sarapis K, Resciniti S, Hall R, Yim K, Tonkovic M, Fitzgerald C, Anixiadis F, Vinh A, Dinh QN, Cronin RA, Hale MW, Wright BJ, Pane M, Tuck CJ, Biesiekierski JR. Evaluation of a probiotic blend on psychosocial health and biomarkers of inflammatory, immune and stress response in adults with subthreshold depression: a double-blind, randomised, placebo-controlled trial. Br J Nutr 2024:1-15. [PMID: 39468832 DOI: 10.1017/s0007114524001703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/30/2024]
Abstract
This study examined the efficacy of a probiotic in reducing depressive symptom severity in people with subthreshold depression. In a double-blind, randomised, placebo-controlled trial, a probiotic (1 × 10^9 live cells per strain: Limosilactobacillus fermentum LF16 (DSM26956), Lacticaseibacillus rhamnosus LR06 (DSM21981), Lactiplantibacillus plantarum LP01 (LMG P-21021) and Bifidobacterium longum 04 (DSM23233)) or placebo was taken daily for 12 weeks. Data were collected at baseline, 6 and 12 weeks including psychological symptom severity (Beck Depression Inventory, BDI; Patient Health Questionnaire, PHQ; Hospital Anxiety Depression Scale, HADS; and Depression Anxiety and Stress Scale, DASS). Biomarkers of glycaemia, inflammation (high-sensitivity C-reactive protein, hs-CRP), antioxidant status (total glutathione (GSH)) and stress (cortisol awakening response, CAR) were also measured. Thirty-nine participants (nineteen probiotic; twenty placebo) were enrolled. There were no significant between-group differences in the examined psychological symptom severity scores, despite certain significant within-group changes observed in both groups from baseline to 6 and/or 12 weeks of follow-up. Regarding biomarkers, the probiotic group showed reduced hs-CRP (-1520; 95 % CI -273·7, -2766·2 ng/dl) and CAR (-0·28; 95 % CI -0·05, -0·51 μg/dl) at 12 weeks, but increased total GSH (3·9; 95 % CI 0·1, 7·5 ng/dl) at 6 weeks, compared with the placebo. The current study reported favourable decreases in depressive symptoms in both groups. Although the within-group changes observed in the probiotic group were supported by favourable inflammatory, antioxidant status and stress biomarker changes compared with the placebo, further research is required to shed more light on the role of gut microbiota modulation on emotional regulation.
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Affiliation(s)
- George Moschonis
- Discipline of Food, Nutrition and Dietetics, Department of Sport, Exercise and Nutrition Sciences, School Allied Health, Human Services and Sport, La Trobe University, Melbourne, VIC3086, Australia
- La Trobe Institute for Sustainable Agriculture & Food (LISAF), La Trobe University, VIC3086, Australia
| | - Katerina Sarapis
- Discipline of Food, Nutrition and Dietetics, Department of Sport, Exercise and Nutrition Sciences, School Allied Health, Human Services and Sport, La Trobe University, Melbourne, VIC3086, Australia
| | - Stephanie Resciniti
- Discipline of Food, Nutrition and Dietetics, Department of Sport, Exercise and Nutrition Sciences, School Allied Health, Human Services and Sport, La Trobe University, Melbourne, VIC3086, Australia
| | - Renate Hall
- Discipline of Food, Nutrition and Dietetics, Department of Sport, Exercise and Nutrition Sciences, School Allied Health, Human Services and Sport, La Trobe University, Melbourne, VIC3086, Australia
| | - Kanny Yim
- Discipline of Food, Nutrition and Dietetics, Department of Sport, Exercise and Nutrition Sciences, School Allied Health, Human Services and Sport, La Trobe University, Melbourne, VIC3086, Australia
| | - Matilda Tonkovic
- Discipline of Food, Nutrition and Dietetics, Department of Sport, Exercise and Nutrition Sciences, School Allied Health, Human Services and Sport, La Trobe University, Melbourne, VIC3086, Australia
| | - Clare Fitzgerald
- Discipline of Food, Nutrition and Dietetics, Department of Sport, Exercise and Nutrition Sciences, School Allied Health, Human Services and Sport, La Trobe University, Melbourne, VIC3086, Australia
| | - Fay Anixiadis
- Discipline of Food, Nutrition and Dietetics, Department of Sport, Exercise and Nutrition Sciences, School Allied Health, Human Services and Sport, La Trobe University, Melbourne, VIC3086, Australia
| | - Antony Vinh
- Centre for Cardiovascular Biology and Disease Research (CCBDR), La Trobe Institute of Medical Science (LIMS), La Trobe University, Melbourne, VIC3086, Australia
- Department of Microbiology, Anatomy, Physiology & Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, VIC3086, Australia
| | - Quynh Nhu Dinh
- Centre for Cardiovascular Biology and Disease Research (CCBDR), La Trobe Institute of Medical Science (LIMS), La Trobe University, Melbourne, VIC3086, Australia
- Department of Microbiology, Anatomy, Physiology & Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, VIC3086, Australia
| | - Rachael A Cronin
- Department of Psychology, Counselling and Therapy, La Trobe University, Albury Wodonga, VIC3690, Australia
| | - Matthew W Hale
- Department of Psychology, Counselling and Therapy, La Trobe University, Melbourne, VIC3086, Australia
| | - Bradley J Wright
- Department of Psychology, Counselling and Therapy, La Trobe University, Melbourne, VIC3086, Australia
| | - Marco Pane
- Probiotical Research srl, Novara, 28100, Italy
| | - Caroline J Tuck
- Discipline of Food, Nutrition and Dietetics, Department of Sport, Exercise and Nutrition Sciences, School Allied Health, Human Services and Sport, La Trobe University, Melbourne, VIC3086, Australia
- Department of Nursing and Allied Health, Swinburne University, Melbourne, VIC3122, Australia
| | - Jessica R Biesiekierski
- Discipline of Food, Nutrition and Dietetics, Department of Sport, Exercise and Nutrition Sciences, School Allied Health, Human Services and Sport, La Trobe University, Melbourne, VIC3086, Australia
- Department of Nutrition, Dietetics and Food, Monash University, Melbourne, VIC3168, Australia
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Teranishi M, Ito M, Huang Z, Nishiyama Y, Masuda A, Mino H, Tachibana M, Inada T, Ohno K. Extremely Low-Frequency Electromagnetic Field (ELF-EMF) Increases Mitochondrial Electron Transport Chain Activities and Ameliorates Depressive Behaviors in Mice. Int J Mol Sci 2024; 25:11315. [PMID: 39457098 PMCID: PMC11508854 DOI: 10.3390/ijms252011315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 10/17/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
Compromised mitochondrial electron transport chain (ETC) activities are associated with depression in humans and rodents. However, the effects of the enhancement of mitochondrial ETC activities on depression remain elusive. We recently reported that an extremely low-frequency electromagnetic field (ELF-EMF) of as low as 10 μT induced hormetic activation of mitochondrial ETC complexes in human/mouse cultured cells and mouse livers. Chronic social defeat stress (CSDS) for 10 consecutive days caused behavioral defects mimicking depression in mice, and using an ELF-EMF for two to six weeks ameliorated them. CSDS variably decreased the mitochondrial ETC proteins in the prefrontal cortex (PFC) in 10 days, which were increased by an ELF-EMF in six weeks. CSDS had no effect on the mitochondrial oxygen consumption rate in the PFC in 10 days, but using an ELF-EMF for six weeks enhanced it. CSDS inactivated SOD2 by enhancing its acetylation and increased lipid peroxidation in the PFC. In contrast, the ELF-EMF activated the Sirt3-FoxO3a-SOD2 pathway and suppressed lipid peroxidation. Furthermore, CSDS increased markers for mitophagy, which was suppressed by the ELF-EMF in six weeks. The ELF-EMF exerted beneficial hormetic effects on mitochondrial energy production, mitochondrial antioxidation, and mitochondrial dynamics in a mouse model of depression. We envisage that an ELF-EMF is a promising therapeutic option for depression.
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Affiliation(s)
- Masaki Teranishi
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; (M.T.); (Z.H.); (Y.N.); (A.M.)
| | - Mikako Ito
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; (M.T.); (Z.H.); (Y.N.); (A.M.)
| | - Zhizhou Huang
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; (M.T.); (Z.H.); (Y.N.); (A.M.)
| | - Yuki Nishiyama
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; (M.T.); (Z.H.); (Y.N.); (A.M.)
| | - Akio Masuda
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; (M.T.); (Z.H.); (Y.N.); (A.M.)
| | - Hiroyuki Mino
- Division of Material Science (Physics), Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan;
| | - Masako Tachibana
- Department of Psychiatry, Nagoya University Hospital, Nagoya 466-8560, Japan;
| | - Toshiya Inada
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;
| | - Kinji Ohno
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; (M.T.); (Z.H.); (Y.N.); (A.M.)
- Graduate School of Nutritional Sciences, Nagoya University of Arts and Sciences, Nisshin 470-0196, Japan
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Du D, Yuan Y, Guan X, Xie Q, Dong Z. Ethylene oxide exposure, inflammatory indicators, and depressive symptoms: a cross-sectional study and mediation analysis based on a non-institutionalized American population. Front Public Health 2024; 12:1445257. [PMID: 39416947 PMCID: PMC11480028 DOI: 10.3389/fpubh.2024.1445257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 09/20/2024] [Indexed: 10/19/2024] Open
Abstract
Background Ethylene oxide (EO) is a volatile compound positively correlated with respiratory and cardiovascular diseases. Currently, evidence suggests that environmental exposure may contribute to depressive symptoms. This study evaluated the correlation between EO exposure and depressive symptoms and investigated whether inflammatory indicators had a mediation effect on this correlation. Methods Patients were enrolled from the National Health and Nutrition Examination Survey during 2013-2016, and 2,764 (49.67% male and 50.33% female) participants were ultimately included. EO exposure was determined by measuring hemoglobin-EO adduct (Hb-EO) concentration due to its long half-life, which was log2-transformed. Depressive symptoms were assessed using the Patient Health Questionnaire-9. Multivariable logistic regression analysis was performed to identify any correlations before and after covariate adjustment. Sensitivity analysis, subgroup analyses, and interaction tests were performed to further evaluate identified correlations. Mediation analysis was conducted to reveal whether specific inflammatory indicators mediated the correlation. Results A high prevalence of depressive symptoms was observed in quartiles with increased levels of EO exposure, and male individuals exhibiting higher Hb-EO levels than female individuals. A positive correlation was observed between EO exposure and depressive symptoms (odds ratio [OR]: 1.439, 95% confidence interval [CI]: 1.310, 1.581), which remained stable even after covariate adjustment (OR: 1.332, 95% CI: 1.148, 1.545). Interaction tests showed significant effects of sex (p < 0.001) and thyroid diseases (p = 0.048) on this correlation. In the mediation analysis, white blood cell (p = 0.010) and neutrophil counts (p = 0.010) exerted a mediating effect, accounting for 13.6 and 11.9%, respectively. Conclusion Increased exposure to EO is associated with an elevated risk of depressive symptoms, where white blood cell and neutrophil counts exert a significant mediating effect. Further prospective studies are required to investigate the potential link among EO, other environmental pollutants, and human mental health.
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Affiliation(s)
- Dongru Du
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Yanling Yuan
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Xuan Guan
- Chengdu Medical College, Chengdu, China
| | - Qinglian Xie
- Department of Outpatient, West China Hospital, Sichuan University, Chengdu, China
| | - Zaiquan Dong
- Mental Health Center, West China Hospital, Sichuan University, Chengdu, China
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Lv S, Zhang G, Lu Y, Zhong X, Huang Y, Ma Y, Yan W, Teng J, Wei S. Pharmacological mechanism of natural antidepressants: The role of mitochondrial quality control. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155669. [PMID: 38696923 DOI: 10.1016/j.phymed.2024.155669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 04/15/2024] [Accepted: 04/21/2024] [Indexed: 05/04/2024]
Abstract
BACKGROUND Depression is a mental illness characterized by persistent sadness and a reduced capacity for pleasure. In clinical practice, SSRIs and other medications are commonly used for therapy, despite their various side effects. Natural products present distinct advantages, including synergistic interactions among multiple components and targeting multiple pathways, suggesting their tremendous potential in depression treatment. Imbalance in mitochondrial quality control (MQC) plays a significant role in the pathology of depression, emphasizing the importance of regulating MQC as a potential intervention strategy in addressing the onset and progression of depression. However, the role and mechanism through which natural products regulate MQC in depression treatments still need to be comprehensively elucidated, particularly in clinical and preclinical settings. PURPOSE This review was aimed to summarize the findings of recent studies and outline the pharmacological mechanisms by which natural products modulate MQC to exert antidepressant effects. Additionally, it evaluated current research limitations and proposed new strategies for future preclinical and clinical applications in the depression domain. METHODS To study the main pharmacological mechanisms underlying the regulation of MQC by natural products in the treatment of depression, we conducted a thorough search across databases such as PubMed, Web of Science, and ScienceDirect databases to classify and summarize the relationship between MQC and depression, as well as the regulatory mechanisms of natural products. RESULTS Numerous studies have shown that irregularities in the MQC system play an important role in the pathology of depression, and the regulation of the MQC system is involved in antidepressant treatments. Natural products mainly regulate the MQC system to induce antidepressant effects by alleviating oxidative stress, balancing ATP levels, promoting mitophagy, maintaining calcium homeostasis, optimizing mitochondrial dynamics, regulating mitochondrial membrane potential, and enhancing mitochondrial biogenesis. CONCLUSIONS We comprehensively summarized the regulation of natural products on the MQC system in antidepressants, providing a unique perspective for the application of natural products within antidepressant therapy. However, extensive efforts are imperative in clinical and preclinical investigations to delve deeper into the mechanisms underlying how antidepressant medications impact MQC, which is crucial for the development of effective antidepressant treatments.
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Affiliation(s)
- Shimeng Lv
- Department of First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Guangheng Zhang
- Department of First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Yitong Lu
- Department of First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Xia Zhong
- Institute of Child and Adolescent Health, School of Public Health, Peking University, Beijing 100191, China
| | - Yufei Huang
- Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Yuexiang Ma
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355,China
| | - Wei Yan
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Jing Teng
- Department of First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250014, China.
| | - Sheng Wei
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; High Level Key Disciplines of Traditional Chinese Medicine: Basic Theory of Traditional Chinese Medicine, National Administration of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; Shandong Provincial Engineering Research Center for the Prevention and Treatment of Major Brain Diseases with Traditional Chinese Medicine (PTMBD), Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
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Bao H, Wang C, Xue X, Hu B, Guo Q. CB1 receptor mediates anesthetic drug ketamine‑induced neuroprotection against glutamate in HT22 cells. Exp Ther Med 2024; 27:268. [PMID: 38756904 PMCID: PMC11097274 DOI: 10.3892/etm.2024.12556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 04/02/2024] [Indexed: 05/18/2024] Open
Abstract
The anesthetic drug, ketamine (KTM) has been shown to induce therapeutic effects against major depressive disorder (MDD), however the related underlying mechanisms remain unclear. In the present study, HT22 neuronal cells were treated with glutamate to imitate oxidative stress injury in MDD, and it was hypothesized that the cannabinoid type 1 (CB1) receptor mediates KTM-induced neuroprotection via ameliorating mitochondrial function in glutamate-treated neuronal cells. Compared with the control, glutamate decreased cell viability and intracellular antioxidants, including glutathione (GSH), catalase and superoxide dismutase 2 levels, and inhibited mitochondrial function simultaneously. Moreover, glutamate increased lactate dehydrogenase release, cellular apoptosis level, cleaved caspase-3 expression and intracellular oxidants, such as reactive oxygen species, oxidized GSH and mitochondrial superoxide in the cells. The presence of KTM, however, significantly decreased the glutamate-induced oxidative stress injury, ameliorated the antioxidant/oxidant levels in the cells, enhanced mitochondrial function and upregulated CB1 receptor expression (P<0.05). Co-administration of the CB1 receptor antagonist AM251 markedly abolished the KTM-induced cytoprotective effects and ameliorations of antioxidant/oxidant levels and mitochondrial function, and also reversed CB1 upregulation (P<0.05). These observations indicated that KTM decreases the oxidative stress injury caused by glutamate in HT22 neuronal cells, and the neuroprotective effects may be mediated by the CB1 receptor.
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Affiliation(s)
- He Bao
- Department of Pharmacy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Chen Wang
- Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Xiaorong Xue
- Department of Pharmacy, Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, Shaanxi 710004, P.R. China
| | - Bin Hu
- Department of Pharmacy, Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, Shaanxi 710004, P.R. China
| | - Qi Guo
- Department of Pharmacy, Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, Shaanxi 710004, P.R. China
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10
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Ceylan D, Arat-Çelik HE, Aksahin IC. Integrating mitoepigenetics into research in mood disorders: a state-of-the-art review. Front Physiol 2024; 15:1338544. [PMID: 38410811 PMCID: PMC10895490 DOI: 10.3389/fphys.2024.1338544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 01/24/2024] [Indexed: 02/28/2024] Open
Abstract
Mood disorders, including major depressive disorder and bipolar disorder, are highly prevalent and stand among the leading causes of disability. Despite the largely elusive nature of the molecular mechanisms underpinning these disorders, two pivotal contributors-mitochondrial dysfunctions and epigenetic alterations-have emerged as significant players in their pathogenesis. This state-of-the-art review aims to present existing data on epigenetic alterations in the mitochondrial genome in mood disorders, laying the groundwork for future research into their pathogenesis. Associations between abnormalities in mitochondrial function and mood disorders have been observed, with evidence pointing to notable changes in mitochondrial DNA (mtDNA). These changes encompass variations in copy number and oxidative damage. However, information on additional epigenetic alterations in the mitochondrial genome remains limited. Recent studies have delved into alterations in mtDNA and regulations in the mitochondrial genome, giving rise to the burgeoning field of mitochondrial epigenetics. Mitochondrial epigenetics encompasses three main categories of modifications: mtDNA methylation/hydroxymethylation, modifications of mitochondrial nucleoids, and mitochondrial RNA alterations. The epigenetic modulation of mitochondrial nucleoids, lacking histones, may impact mtDNA function. Additionally, mitochondrial RNAs, including non-coding RNAs, present a complex landscape influencing interactions between the mitochondria and the nucleus. The exploration of mitochondrial epigenetics offers valuable perspectives on how these alterations impact neurodegenerative diseases, presenting an intriguing avenue for research on mood disorders. Investigations into post-translational modifications and the role of mitochondrial non-coding RNAs hold promise to unravel the dynamics of mitoepigenetics in mood disorders, providing crucial insights for future therapeutic interventions.
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Affiliation(s)
- Deniz Ceylan
- Department of Psychiatry, School of Medicine, Koç University, Istanbul, Türkiye
- Koç University Research Center for Translational Medicine (KUTTAM), Affective Laboratory, Istanbul, Türkiye
| | | | - Izel Cemre Aksahin
- Koç University Research Center for Translational Medicine (KUTTAM), Affective Laboratory, Istanbul, Türkiye
- Graduate School of Health Sciences, Koç University, Istanbul, Türkiye
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11
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Zhang G, Lv S, Zhong X, Li X, Yi Y, Lu Y, Yan W, Li J, Teng J. Ferroptosis: a new antidepressant pharmacological mechanism. Front Pharmacol 2024; 14:1339057. [PMID: 38259274 PMCID: PMC10800430 DOI: 10.3389/fphar.2023.1339057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 12/15/2023] [Indexed: 01/24/2024] Open
Abstract
The incidence rate of depression, a mental disorder, is steadily increasing and has the potential to become a major global disability factor. Given the complex pathological mechanisms involved in depression, the use of conventional antidepressants may lead to severe complications due to their side effects. Hence, there is a critical need to explore the development of novel antidepressants. Ferroptosis, a newly recognized form of cell death, has been found to be closely linked to the onset of depression. Several studies have indicated that certain active ingredients can ameliorate depression by modulating the ferroptosis signaling pathway. Notably, traditional Chinese medicine (TCM) active ingredients and TCM prescriptions have demonstrated promising antidepressant effects in previous investigations owing to their unique advantages in antidepressant therapy. Building upon these findings, our objective was to review recent relevant research and provide new insights and directions for the development and application of innovative antidepressant strategies.
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Affiliation(s)
- Guangheng Zhang
- Department of First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shimeng Lv
- Department of First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xia Zhong
- Department of First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiangyu Li
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yunhao Yi
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yitong Lu
- Department of First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wei Yan
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jiamin Li
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jing Teng
- Department of First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
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12
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Ceylan D, Karacicek B, Tufekci KU, Aksahin IC, Senol SH, Genc S. Mitochondrial DNA oxidation, methylation, and copy number alterations in major and bipolar depression. Front Psychiatry 2023; 14:1304660. [PMID: 38161720 PMCID: PMC10755902 DOI: 10.3389/fpsyt.2023.1304660] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 11/20/2023] [Indexed: 01/03/2024] Open
Abstract
Background Mood disorders are common disabling psychiatric disorders caused by both genetic and environmental factors. Mitochondrial DNA (mtDNA) modifications and epigenetics are promising areas of research in depression since mitochondrial dysfunction has been associated with depression. In this study we aimed to investigate the mtDNA changes in depressive disorder (MDD) and bipolar disorder (BD). Methods Displacement loop methylation (D-loop-met), relative mtDNA copy number (mtDNA-cn) and mtDNA oxidation (mtDNA-oxi) were investigated in DNA samples of individuals with MDD (n = 34), BD (n = 23), and healthy controls (HC; n = 40) using the Real-Time Polymerase Chain Reaction (RT-PCR). Blood samples were obtained from a subset of individuals with MDD (n = 15) during a depressive episode (baseline) and after remission (8th week). Results The study groups exhibited significant differences in D-loop-met (p = 0.020), while relative mtDNA-cn and mtDNA-oxi showed comparable results. During the remission phase (8th week), there were lower levels of relative mtDNA-cn (Z = -2.783, p = 0.005) and D-loop-met (Z = -3.180, p = 0.001) compared to the acute MDD baseline, with no significant change in mtDNA-oxi levels (Z = -1.193, p = 0.233). Conclusion Our findings indicate significantly increased D-loop methylation in MDD compared to BD and HCs, suggesting distinct mtDNA modifications in these conditions. Moreover, the observed alterations in relative mtDNA-cn and D-loop-met during remission suggest a potential role of mtDNA alterations in the pathophysiology of MDD. Future studies may provide valuable insights into the dynamics of mtDNA modifications in both disorders and their response to treatment.
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Affiliation(s)
- Deniz Ceylan
- Affective Laboratory, Koç University Research Center for Translational Medicine, Istanbul, Türkiye
- Department of Psychiatry, Koç University Hospital, Istanbul, Türkiye
| | - Bilge Karacicek
- Izmir Biomedicine and Genome Center, Genç Lab, Izmir, Türkiye
| | - Kemal Ugur Tufekci
- Brain and Neuroscience Research and Application Center, Izmir Demokrasi University, Izmir, Türkiye
- Vocational School of Health Services, Izmir Democracy University, Izmir, Türkiye
| | - Izel Cemre Aksahin
- Affective Laboratory, Koç University Research Center for Translational Medicine, Istanbul, Türkiye
- Graduate School of Health Sciences, Koç University, Istanbul, Türkiye
| | - Sevin Hun Senol
- Department of Psychiatry, Koç University Hospital, Istanbul, Türkiye
| | - Sermin Genc
- Izmir Biomedicine and Genome Center, Genç Lab, Izmir, Türkiye
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Li W, Zhu L, Chen Y, Zhuo Y, Wan S, Guo R. Association between mitochondrial DNA levels and depression: a systematic review and meta-analysis. BMC Psychiatry 2023; 23:866. [PMID: 37993802 PMCID: PMC10664364 DOI: 10.1186/s12888-023-05358-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 11/07/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Mitochondrial dysfunction leading to disturbances in energy metabolism has emerged as one of the risk factors in the pathogenesis of depression. Numerous studies have identified alterations in the content of mitochondrial DNA (mtDNA) in peripheral blood and cerebrospinal fluid of individuals with depression. Researchers have sought to establish a clear association between mtDNA and depression. Consequently, we conducted a comprehensive meta-analysis to assess the existing evidence regarding the impact of mtDNA on depression. METHODS This study conducted a thorough search of the following databases up to March 13, 2023: PubMed, Embase, the Cochrane Library, the Web of Science, Wanfang Database, SINOMED, the China Science and Technology Journal Database, and China National Knowledge Infrastructure. The meta-analysis was carried out using RevMan (version 5.4) and Stata (version 16.0) software. In addition, publication bias was assessed with funnel plots, Begg's test and Egger's test. RESULTS Our analysis included data from 10 articles, including 12 studies for further examination. A total of 1400 participants were included in this study, comprising 709 (including 300 males and 409 females) patients with depression and 691 (including 303 males and 388 females) healthy controls. The average age of depressed patients was (42.98 ± 2.55) years, and the average age of healthy people was (41.71 ± 2.6) years. The scales used to assess outcomes are Hamilton-rating scale for Depression(4 articles), Montgomery-Asberg Depression Rating Scale(3 articles), and Mini-Internatioal Neuropsychiatric Interview (1 articles). The meta-analysis revealed significantly higher levels of mtDNA in circulating blood samples and skin fibroblasts of individuals with depression in comparison to healthy controls [standardized mean difference(SMD) = 0.42, 95% confidence intervals(CI): 0.16, 0.67]. CONCLUSIONS Our study concludes that there is a significant (p < 0.05) increase in mtDNA levels in serum, plasma, and cerebrospinal fluid in individuals with depression. These findings suggest that mtDNA could serve as a potential biomarker for diagnosing depression. REGISTRATION NUMBER PROSPERO CRD42023414285.
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Affiliation(s)
- Wenhui Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Lingqun Zhu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing Key Laboratory of Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Yi Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Yudi Zhuo
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Shurun Wan
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Rongjuan Guo
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078, China.
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14
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Czarny P, Ziółkowska S, Kołodziej Ł, Watała C, Wigner-Jeziorska P, Bliźniewska-Kowalska K, Wachowska K, Gałecka M, Synowiec E, Gałecki P, Bijak M, Szemraj J, Śliwiński T. Single-Nucleotide Polymorphisms in Genes Maintaining the Stability of Mitochondrial DNA Affect the Occurrence, Onset, Severity and Treatment of Major Depressive Disorder. Int J Mol Sci 2023; 24:14752. [PMID: 37834200 PMCID: PMC10573273 DOI: 10.3390/ijms241914752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 09/26/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
One of the key features of major depressive disorder (MDD, depression) is increased oxidative stress manifested by elevated levels of mtROS, a hallmark of mitochondrial dysfunction, which can arise from mitochondrial DNA (mtDNA) damage. Thus, the current study explores possibility that the single-nucleotide polymorphisms (SNPs) of genes encoding the three enzymes that are thought to be implicated in the replication, repair or degradation of mtDNA, i.e., POLG, ENDOG and EXOG, have an impact on the occurrence, onset, severity and treatment of MDD. Five SNPs were selected: EXOG c.-188T > G (rs9838614), EXOG c.*627G > A (rs1065800), POLG c.-1370T > A (rs1054875), ENDOG c.-394T > C (rs2977998) and ENDOG c.-220C > T (rs2997922), while genotyping was performed on 538 DNA samples (277 cases and 261 controls) using TaqMan probes. All SNPs of EXOG and ENDOG modulated the risk of depression, but the strongest effect was observed for rs1065800, while rs9838614 and rs2977998 indicate that they might influence the severity of symptoms, and, to a lesser extent, treatment effectiveness. Although the SNP located in POLG did not affect occurrence of the disease, the result suggests that it may influence the onset and treatment outcome. These findings further support the hypothesis that mtDNA damage and impairment in its metabolism play a crucial role not only in the development, but also in the treatment of depression.
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Affiliation(s)
- Piotr Czarny
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland; (S.Z.); (J.S.)
| | - Sylwia Ziółkowska
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland; (S.Z.); (J.S.)
| | - Łukasz Kołodziej
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 92-215 Lodz, Poland; (Ł.K.)
| | - Cezary Watała
- Department of Haemostatic Disorders, Medical University of Lodz, 92-215 Lodz, Poland;
| | - Paulina Wigner-Jeziorska
- Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, 90-136 Lodz, Poland;
| | | | - Katarzyna Wachowska
- Department of Adult Psychiatry, Medical University of Lodz, 91-229 Lodz, Poland; (K.B.-K.); (K.W.); (P.G.)
| | - Małgorzata Gałecka
- Department of Psychotherapy, Medical University of Lodz, 91-229 Lodz, Poland;
| | - Ewelina Synowiec
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 92-215 Lodz, Poland; (Ł.K.)
| | - Piotr Gałecki
- Department of Adult Psychiatry, Medical University of Lodz, 91-229 Lodz, Poland; (K.B.-K.); (K.W.); (P.G.)
| | - Michał Bijak
- Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, 90-136 Lodz, Poland;
| | - Janusz Szemraj
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland; (S.Z.); (J.S.)
| | - Tomasz Śliwiński
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 92-215 Lodz, Poland; (Ł.K.)
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15
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Ochi S, Roy B, Prall K, Shelton RC, Dwivedi Y. Strong associations of telomere length and mitochondrial copy number with suicidality and abuse history in adolescent depressed individuals. Mol Psychiatry 2023; 28:3920-3929. [PMID: 37735501 PMCID: PMC10730407 DOI: 10.1038/s41380-023-02263-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 08/30/2023] [Accepted: 09/08/2023] [Indexed: 09/23/2023]
Abstract
Major depressive disorder (MDD) is highly prevalent in adolescents and is a major risk factor for suicidality. Recent evidence shows that accelerated cellular senescence/aging is associated with psychiatric illness, including depression, in adults. The present study examined if the relationships of telomere length (TL) and mitochondrial DNA copy number (mtDNAcn), two critical indicators of cellular senescence/aging, are altered in depressed adolescents and whether these alterations are associated with suicidality, early-life adversities, and other co-occuring factors. In genomic DNA isolated from 53 adolescents (ages 16-19, 19 MDD with suicide attempt/suicidal ideation [MDD + SI/SA], 14 MDD without SA/SI [MDD-SI/SA], and 20 healthy controls [HC]), TL and mtDNAcn were measured as the ratio between the number of telomere repeats and that of a single-copy nuclear-hemoglobin [HBG] gene or the amount of mtDNA (NADH dehydrogenase, subunit 1) relative to HBG. Our data show that TL was significantly lower, and mtDNAcn was significantly higher in the total MDD group than HC. TL was significantly lower and mtDNAcn was significantly higher in the MDD + SA/SI group than in the HC, whereas there were no differences in the MDD-SI/SA group. TL was positively correlated with mtDNAcn in both HC and MDD-SA/SI groups; however, TL was negatively correlated with mtDNAcn in MDD + SA/SI. Furthermore, TL was negatively correlated with the severity of both depression and anxiety, while mtDNAcn was positively correlated with the severity of prior emotional abuse. Our study indicates that cellular senescence is more advanced in depressed adolescents with suicidal ideation and that childhood emotional abuse may participate in such a process.
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Affiliation(s)
- Shinichiro Ochi
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
- Department of Neuropsychiatry, Molecules and Function, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Bhaskar Roy
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Kevin Prall
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Richard C Shelton
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Yogesh Dwivedi
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
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16
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Khan M, Baussan Y, Hebert-Chatelain E. Connecting Dots between Mitochondrial Dysfunction and Depression. Biomolecules 2023; 13:695. [PMID: 37189442 PMCID: PMC10135685 DOI: 10.3390/biom13040695] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/10/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
Mitochondria are the prime source of cellular energy, and are also responsible for important processes such as oxidative stress, apoptosis and Ca2+ homeostasis. Depression is a psychiatric disease characterized by alteration in the metabolism, neurotransmission and neuroplasticity. In this manuscript, we summarize the recent evidence linking mitochondrial dysfunction to the pathophysiology of depression. Impaired expression of mitochondria-related genes, damage to mitochondrial membrane proteins and lipids, disruption of the electron transport chain, higher oxidative stress, neuroinflammation and apoptosis are all observed in preclinical models of depression and most of these parameters can be altered in the brain of patients with depression. A deeper knowledge of the depression pathophysiology and the identification of phenotypes and biomarkers with respect to mitochondrial dysfunction are needed to help early diagnosis and the development of new treatment strategies for this devastating disorder.
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Affiliation(s)
- Mehtab Khan
- Department of Biology, University of Moncton, Moncton, NB E1A 3E9, Canada
- Mitochondrial Signaling and Pathophysiology, University of Moncton, Moncton, NB E1A 3E9, Canada
| | - Yann Baussan
- Department of Biology, University of Moncton, Moncton, NB E1A 3E9, Canada
- Mitochondrial Signaling and Pathophysiology, University of Moncton, Moncton, NB E1A 3E9, Canada
| | - Etienne Hebert-Chatelain
- Department of Biology, University of Moncton, Moncton, NB E1A 3E9, Canada
- Mitochondrial Signaling and Pathophysiology, University of Moncton, Moncton, NB E1A 3E9, Canada
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17
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Ait Tayeb AEK, Poinsignon V, Chappell K, Bouligand J, Becquemont L, Verstuyft C. Major Depressive Disorder and Oxidative Stress: A Review of Peripheral and Genetic Biomarkers According to Clinical Characteristics and Disease Stages. Antioxidants (Basel) 2023; 12:antiox12040942. [PMID: 37107318 PMCID: PMC10135827 DOI: 10.3390/antiox12040942] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/30/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
Major depressive disorder (MDD) is currently the main cause of disability worldwide, but its pathophysiology remains largely unknown, especially given its high heterogeneity in terms of clinical phenotypes and biological characteristics. Accordingly, its management is still poor. Increasing evidence suggests that oxidative stress, measured on various matrices such as serum, plasma or erythrocytes, has a critical role in MDD. The aim of this narrative review is to identify serum, plasma and erythrocyte biomarkers of oxidative stress in MDD patients according to disease stage and clinical features. Sixty-three articles referenced on PubMed and Embase between 1 January 1991, and 31 December 2022, were included. Modifications to antioxidant enzymes (mainly glutathione peroxidase and superoxide dismutase) in MDD were highlighted. Non-enzymatic antioxidants (mainly uric acid) were decreased in depressed patients compared to healthy controls. These changes were associated with an increase in reactive oxygen species. Therefore, increased oxidative damage products (principally malondialdehyde, protein carbonyl content and 8-hydroxy-2'-deoxyguanosine) were present in MDD patients. Specific modifications could be identified according to disease stages and clinical features. Interestingly, antidepressant treatment corrected these changes. Accordingly, in patients in remission from depression, oxidative stress markers were globally normalized. This narrative review suggests the particular interest of oxidative stress biomarkers for MDD care that may contribute to the heterogeneity of the disease and provide the opportunity to find new therapeutic targets.
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Affiliation(s)
- Abd El Kader Ait Tayeb
- Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie de Bicêtre, Hôpitaux Universitaires Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, F-94275 Le Kremlin Bicêtre, France
| | - Vianney Poinsignon
- Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie de Bicêtre, Hôpitaux Universitaires Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, F-94275 Le Kremlin Bicêtre, France
- CESP, MOODS Team, INSERM UMR 1018, Faculté de Médecine, Universitaires Paris-Saclay, F-94275 Le Kremlin Bicêtre, France
| | - Kenneth Chappell
- CESP, MOODS Team, INSERM UMR 1018, Faculté de Médecine, Universitaires Paris-Saclay, F-94275 Le Kremlin Bicêtre, France
| | - Jérôme Bouligand
- Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie de Bicêtre, Hôpitaux Universitaires Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, F-94275 Le Kremlin Bicêtre, France
- INSERM UMR-S U1185, Faculté de Médecine, Universitaires Paris-Saclay, F-94275 Le Kremlin Bicêtre, France
| | - Laurent Becquemont
- CESP, MOODS Team, INSERM UMR 1018, Faculté de Médecine, Universitaires Paris-Saclay, F-94275 Le Kremlin Bicêtre, France
- Centre de Recherche Clinique, Hôpitaux Universitaires Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, F-94275 Le Kremlin Bicêtre, France
| | - Céline Verstuyft
- Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie de Bicêtre, Hôpitaux Universitaires Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, F-94275 Le Kremlin Bicêtre, France
- CESP, MOODS Team, INSERM UMR 1018, Faculté de Médecine, Universitaires Paris-Saclay, F-94275 Le Kremlin Bicêtre, France
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18
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Ryan KM, Doody E, McLoughlin DM. Whole blood mitochondrial DNA copy number in depression and response to electroconvulsive therapy. Prog Neuropsychopharmacol Biol Psychiatry 2023; 121:110656. [PMID: 36216200 DOI: 10.1016/j.pnpbp.2022.110656] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/28/2022] [Accepted: 10/03/2022] [Indexed: 11/05/2022]
Abstract
Mitochondrial dysfunction may play a role in various psychiatric conditions. Mitochondrial DNA copy number (mtDNAcn), the ratio of mitochondrial DNA to nuclear DNA, represents an attractive marker of mitochondrial health that is easily measured from stored DNA samples, and has been shown to be altered in depression. In this study, we measured mtDNAcn in whole blood samples from medicated patients with depression (n = 100) compared to healthy controls (n = 89) and determined the relationship between mtDNAcn and depression severity and the therapeutic response to electroconvulsive therapy (ECT). We also explored the relationship between mtDNAcn and telomere length and inflammatory markers. Our results show that mtDNAcn was significantly elevated in blood from patients with depression when compared to control samples, and this result survived statistical adjustment for potential confounders (p = 0.002). mtDNAcn was significantly elevated in blood from subgroups of patients with non-psychotic or unipolar depression. There was no difference in mtDNAcn noted in subgroups of ECT remitters/non-remitters or responders/non-responders. Moreover, mtDNAcn was not associated with depression severity, telomere length, or circulating inflammatory marker concentrations. Overall, our results show that mtDNAcn is elevated in blood from patients with depression, though whether this translates to mitochondrial function is unknown. Further work is required to clarify the contribution of mitochondria and mtDNA to the pathophysiology of depression and the therapeutic response to antidepressant treatments.
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Affiliation(s)
- Karen M Ryan
- Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland; Department of Psychiatry, St. Patrick's University Hospital, Trinity College Dublin, James Street, Dublin 8, Ireland
| | - Eimear Doody
- Department of Psychiatry, St. Patrick's University Hospital, Trinity College Dublin, James Street, Dublin 8, Ireland
| | - Declan M McLoughlin
- Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland; Department of Psychiatry, St. Patrick's University Hospital, Trinity College Dublin, James Street, Dublin 8, Ireland.
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19
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Sapsford TP, Johnson SR, Headrick JP, Branjerdporn G, Adhikary S, Sarfaraz M, Stapelberg NJC. Forgetful, sad and old: Do vascular cognitive impairment and depression share a common pre-disease network and how is it impacted by ageing? J Psychiatr Res 2022; 156:611-627. [PMID: 36372004 DOI: 10.1016/j.jpsychires.2022.10.071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 10/25/2022] [Accepted: 10/31/2022] [Indexed: 11/07/2022]
Abstract
Vascular cognitive impairment (VCI) and depression frequently coexist in geriatric populations and reciprocally increase disease risks. We assert that a shared pre-disease state of the psycho-immune-neuroendocrine (PINE) network model mechanistically explains bidirectional associations between VCI and depression. Five pathophysiological sub-networks are identified that are shared by VCI and depression: neuroinflammation, kynurenine pathway imbalance, hypothalamic-pituitary-adrenal (HPA) axis overactivity, impaired neurotrophic support and cerebrovascular dysfunction. These do not act independently, and their complex interactions necessitate a systems biology approach to better define disease pathogenesis. The PINE network is already established in the context of non-communicable diseases (NCDs) such as depression, hypertension, atherosclerosis, coronary heart disease and type 2 diabetes mellitus. We build on previous literature to specifically explore mechanistic links between MDD and VCI in the context of PINE pathways and discuss key mechanistic commonalities linking these comorbid conditions and identify a common pre-disease state which precedes transition to VCI and MDD. We expand the model to incorporate bidirectional interactions with biological ageing. Diathesis factors for both VCI and depression feed into this network and the culmination of shared mechanisms (on an ageing substrate) lead to a critical network transition to one or both disease states. A common pre-disease state underlying VCI and depression can provide clinicians a unique opportunity for early risk assessment and intervention in disease development. Establishing the mechanistic elements and systems biology of this network can reveal early warning or predictive biomarkers together with novel therapeutic targets. Integrative studies are recommended to elucidate the dynamic networked biology of VCI and depression over time.
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Affiliation(s)
- Timothy P Sapsford
- Griffith University School of Medicine, Gold Coast, Queensland, Australia; Gold Coast Hospital and Health Service, Gold Coast, Queensland, Australia
| | - Susannah R Johnson
- Gold Coast Hospital and Health Service, Gold Coast, Queensland, Australia
| | - John P Headrick
- Griffith University School of Medicine, Gold Coast, Queensland, Australia
| | - Grace Branjerdporn
- Gold Coast Hospital and Health Service, Gold Coast, Queensland, Australia.
| | - Sam Adhikary
- Mater Young Adult Health Centre, Mater Hospital, Brisbane, Queensland, Australia
| | - Muhammad Sarfaraz
- Gold Coast Hospital and Health Service, Gold Coast, Queensland, Australia
| | - Nicolas J C Stapelberg
- Gold Coast Hospital and Health Service, Gold Coast, Queensland, Australia; Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Queensland, Australia
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20
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Zhao L, Sun Y, Cao R, Wu X, Huang T, Peng W. Non-linear association between composite dietary antioxidant index and depression. Front Public Health 2022; 10:988727. [PMID: 36311643 PMCID: PMC9609418 DOI: 10.3389/fpubh.2022.988727] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 09/26/2022] [Indexed: 01/26/2023] Open
Abstract
Background Growing evidence has shown that the antioxidant diet is a protective factor against depression. However, the relationship between the Composite Dietary Antioxidant Index (CDAI), an important measure of antioxidant diet, and depression has received little attention. Therefore, we investigated the relationship between CDAI and depression through a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. Methods The association between CDAI and depression was investigated using a weighted multiple logistic regression model with subgroup analysis. Non-linear correlations were explored using fitted smoothing curves. And we used a recursive method to figure out the turning point and build a weighted two-piece linear regression model. Results In the multivariate logistic regression model with full adjustment for confounding variables, the ORs (95% CI) for the association between CDAI and depression were 0.83 (0.78, 0.88). Moreover, a non-linear association was found, with 0.16 being the inflection point. Before the inflection point, each unit increase in CDAI was associated with a 30% decrease in the risk of depression. After the inflection point, the risk of depression was found to be reduced by 11% for each unit increase. None of the interactions in all subgroup analyses were statistically significant. Conclusions Our study highlighted a negative non-linear association between CDAI and depression in a nationally representative sample of US adults. Further clinical and basic research is needed to explore their association better.
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Affiliation(s)
- Leiyong Zhao
- Department of Psychosomatic Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yiyan Sun
- The First Clinical College of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Renshuang Cao
- The First Clinical College of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xueqiang Wu
- The First Clinical College of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Tianjiao Huang
- The First Clinical College of Shandong University of Traditional Chinese Medicine, Jinan, China,*Correspondence: Tianjiao Huang
| | - Wei Peng
- Department of Psychosomatic Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China,Wei Peng
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21
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Jorgensen A, Baago IB, Rygner Z, Jorgensen MB, Andersen PK, Kessing LV, Poulsen HE. Association of Oxidative Stress-Induced Nucleic Acid Damage With Psychiatric Disorders in Adults: A Systematic Review and Meta-analysis. JAMA Psychiatry 2022; 79:920-931. [PMID: 35921094 PMCID: PMC9350850 DOI: 10.1001/jamapsychiatry.2022.2066] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
IMPORTANCE Nucleic acid damage from oxidative stress (NA-OXS) may be a molecular mechanism driving the severely increased morbidity and mortality from somatic causes in adults with psychiatric disorders. OBJECTIVE To systematically retrieve and analyze data on NA-OXS across the psychiatric disorder diagnostic spectrum. DATA SOURCES The PubMed, Embase, and PsycINFO databases were searched from inception to November 16, 2021. A hand search of reference lists of relevant articles was also performed. STUDY SELECTION Key study inclusion criteria in this meta-analysis were as follows: adult human study population, measurement of any marker of DNA or RNA damage from oxidative stress, and either a (1) cross-sectional design comparing patients with psychiatric disorders (any diagnosis) with a control group or (2) prospective intervention. Two authors screened the studies, and 2 senior authors read the relevant articles in full and assessed them for eligibility. DATA EXTRACTION AND SYNTHESIS The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two authors performed data extraction independently, and a senior coauthor was consulted in cases of disagreement. Data were synthesized with random-effects and multilevel meta-analyses. MAIN OUTCOMES AND MEASURES The predefined hypothesis was that individuals with psychiatric disorders have increased NA-OXS levels. The main outcome was the standardized mean differences (SMDs) among patients and controls in nucleic acid oxidation markers compared across diagnostic groups. Analyses were divided into combinations of biological matrices and nucleic acids. RESULTS Eighty-two studies fulfilled the inclusion criteria, comprising 205 patient vs control group comparisons and a total of 10 151 patient and 10 532 control observations. Overall, the data showed that patients with psychiatric disorders had higher NA-OXS levels vs controls across matrices and molecules. Pooled effect sizes ranged from moderate for urinary DNA markers (SMD = 0.44 [95% CI, 0.20-0.68]; P < .001) to very large for blood cell DNA markers (SMD = 1.12 [95% CI, 0.69-1.55; P < .001). Higher NA-OXS levels were observed among patients with dementias followed by psychotic and bipolar disorders. Sensitivity analyses excluding low-quality studies did not materially alter the results. Intervention studies were few and too heterogenous for meaningful meta-analysis. CONCLUSIONS AND RELEVANCE The results of this meta-analysis suggest that there is an association with increased NA-OXS levels in individuals across the psychiatric disorder diagnostic spectrum. NA-OXS may play a role in the somatic morbidity and mortality observed among individuals with psychiatric disorders.
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Affiliation(s)
- Anders Jorgensen
- Psychiatric Center Copenhagen, Mental Health Services Copenhagen, Copenhagen, Denmark,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ida Bendixen Baago
- Psychiatric Center Copenhagen, Mental Health Services Copenhagen, Copenhagen, Denmark
| | - Zerlina Rygner
- Psychiatric Center Copenhagen, Mental Health Services Copenhagen, Copenhagen, Denmark,Department of Cardiology, Copenhagen University Hospital, Hillerød, Denmark,Department of Endocrinology, Copenhagen University Hospital, Hillerød, Denmark
| | - Martin Balslev Jorgensen
- Psychiatric Center Copenhagen, Mental Health Services Copenhagen, Copenhagen, Denmark,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | | | - Lars Vedel Kessing
- Psychiatric Center Copenhagen, Mental Health Services Copenhagen, Copenhagen, Denmark,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Henrik Enghusen Poulsen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark,Department of Cardiology, Copenhagen University Hospital, Hillerød, Denmark,Department of Endocrinology, Copenhagen University Hospital, Hillerød, Denmark
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22
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Durand M, Nagot N, Michel L, Le SM, Duong HT, Vallo R, Vizeneux A, Rapoud D, Giang HT, Quillet C, Thanh NTT, Hai Oanh KT, Vinh VH, Feelemyer J, Vande Perre P, Minh KP, Laureillard D, Des Jarlais D, Molès JP. Mental Disorders Are Associated With Leukocytes Telomere Shortening Among People Who Inject Drugs. Front Psychiatry 2022; 13:846844. [PMID: 35782414 PMCID: PMC9247253 DOI: 10.3389/fpsyt.2022.846844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 05/12/2022] [Indexed: 11/13/2022] Open
Abstract
Premature biological aging, assessed by shorter telomere length (TL) and mitochondrial DNA (mtDNA) alterations, has been reported among people with major depressive disorders or psychotic disorders. However, these markers have never been assessed together among people who inject drugs (PWIDs), although mental disorders are highly prevalent in this population, which, in addition, is subject to other aggravating exposures. Diagnosis of mental disorders was performed by a psychiatrist using the Mini International Neuropsychiatric Interview test among active PWIDs in Haiphong, Vietnam. mtDNA copy number (MCN), mtDNA deletion, and TL were assessed by quantitative PCR and compared to those without any mental disorder. We next performed a multivariate analysis to identify risk factors associated with being diagnosed with a major depressive episode (MDE) or a psychotic syndrome (PS). In total, 130 and 136 PWIDs with and without psychiatric conditions were analyzed. Among PWIDs with mental disorders, 110 and 74 were diagnosed with MDE and PS, respectively. TL attrition was significantly associated with hepatitis C virus-infected PWIDs with MDE or PS (adjusted odds ratio [OR]: 0.53 [0.36; 0.80] and 0.59 [0.39; 0.88], respectively). TL attrition was even stronger when PWIDs cumulated at least two episodes of major depressive disorders. On the other hand, no difference was observed in mtDNA alterations between groups. The telomeric age difference with drug users without a diagnosis of psychiatric condition was estimated during 4.2-12.8 years according to the number of MDEs, making this group more prone to age-related diseases.
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Affiliation(s)
- Mélusine Durand
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, Montpellier, France
| | - Nicolas Nagot
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, Montpellier, France
| | - Laurent Michel
- Pierre Nicole Center, CESP UMR 1018, Paris-Saclay University, Paris, France
| | - Sao Mai Le
- Faculty of Public Health, Hai Phong University of Medicine and Pharmacy, Hai Phong, Vietnam
| | - Huong Thi Duong
- Faculty of Public Health, Hai Phong University of Medicine and Pharmacy, Hai Phong, Vietnam
| | - Roselyne Vallo
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, Montpellier, France
| | - Amélie Vizeneux
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, Montpellier, France
| | - Delphine Rapoud
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, Montpellier, France
| | - Hoang Thi Giang
- Faculty of Public Health, Hai Phong University of Medicine and Pharmacy, Hai Phong, Vietnam
| | - Catherine Quillet
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, Montpellier, France
| | | | | | - Vu Hai Vinh
- Infectious and Tropical Diseases Department, Viet Tiep Hospital, Hai Phong, Vietnam
| | - Jonathan Feelemyer
- School of Global Public Health, New York University, New York, NY, United States
| | - Philippe Vande Perre
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, Montpellier, France
| | - Khue Pham Minh
- Faculty of Public Health, Hai Phong University of Medicine and Pharmacy, Hai Phong, Vietnam
| | - Didier Laureillard
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, Montpellier, France.,Infectious and Tropical Diseases Department, Caremeau University Hospital, Nîmes, France
| | - Don Des Jarlais
- School of Global Public Health, New York University, New York, NY, United States
| | - Jean-Pierre Molès
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, Montpellier, France
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23
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Casaril AM, Dantzer R, Bas-Orth C. Neuronal Mitochondrial Dysfunction and Bioenergetic Failure in Inflammation-Associated Depression. Front Neurosci 2021; 15:725547. [PMID: 34790089 PMCID: PMC8592286 DOI: 10.3389/fnins.2021.725547] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 10/12/2021] [Indexed: 01/28/2023] Open
Abstract
Depression is a leading cause of disability and affects more than 4% of the population worldwide. Even though its pathophysiology remains elusive, it is now well accepted that peripheral inflammation might increase the risk of depressive episodes in a subgroup of patients. However, there is still insufficient knowledge about the mechanisms by which inflammation induces alterations in brain function. In neurodegenerative and neuroinflammatory diseases, extensive studies have reported that inflammation negatively impacts mitochondrial health, contributing to excitotoxicity, oxidative stress, energy deficits, and eventually neuronal death. In addition, damaged mitochondria can release a wide range of damage-associated molecular patterns that are potent activators of the inflammatory response, creating a feed-forward cycle between oxidative stress, mitochondrial impairment, inflammation, and neuronal dysfunction. Surprisingly, the possible involvement of this vicious cycle in the pathophysiology of inflammation-associated depression remains understudied. In this mini-review we summarize the research supporting the association between neuroinflammation, mitochondrial dysfunction, and bioenergetic failure in inflammation-associated depression to highlight the relevance of further studies addressing this crosstalk.
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Affiliation(s)
- Angela Maria Casaril
- Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany.,Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Robert Dantzer
- Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Carlos Bas-Orth
- Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany
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24
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Tripathi A, Scaini G, Barichello T, Quevedo J, Pillai A. Mitophagy in depression: Pathophysiology and treatment targets. Mitochondrion 2021; 61:1-10. [PMID: 34478906 PMCID: PMC8962570 DOI: 10.1016/j.mito.2021.08.016] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/16/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023]
Abstract
Mitochondria, the 'powerhouse' of eukaryotic cells, play a key role in cellular homeostasis. However, defective mitochondria increase mitochondrial ROS (mtROS) production and cell-free mitochondrial DNA (mtDNA) release, leading to increased inflammation. Mitophagy is a vital pathway, which selectively removes defective mitochondria through the process of autophagy. Thus, an impairment in the mitophagy pathway might trigger the gradual accumulation of defective mitochondria. Accumulating evidence suggest that inflammation and mitochondrial dysfunction are linked to the pathogenesis of depression. In this article, we have reviewed the role of impaired mitophagy as a contributing factor in depression pathophysiology. Further, we have discussed the potential therapeutic interventions aimed at modulating mitophagy in depression.
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Affiliation(s)
- Ashutosh Tripathi
- Pathophysiology of Neuropsychiatric Disorders Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA; Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Giselli Scaini
- Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Tatiana Barichello
- Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA; Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - João Quevedo
- Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA; Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA; Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA; Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Anilkumar Pillai
- Pathophysiology of Neuropsychiatric Disorders Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA; Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA; Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA; Research and Development, Charlie Norwood VA Medical Center, Augusta, GA, USA.
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25
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Moya GE, Rivera PD, Dittenhafer-Reed KE. Evidence for the Role of Mitochondrial DNA Release in the Inflammatory Response in Neurological Disorders. Int J Mol Sci 2021; 22:7030. [PMID: 34209978 PMCID: PMC8268735 DOI: 10.3390/ijms22137030] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/25/2021] [Accepted: 06/26/2021] [Indexed: 12/21/2022] Open
Abstract
Mitochondria are regarded as the metabolic centers of cells and are integral in many other cell processes, including the immune response. Each mitochondrion contains numerous copies of mitochondrial DNA (mtDNA), a small, circular, and bacterial-like DNA. In response to cellular damage or stress, mtDNA can be released from the mitochondrion and trigger immune and inflammatory responses. mtDNA release into the cytosol or bloodstream can occur as a response to hypoxia, sepsis, traumatic injury, excitatory cytotoxicity, or drastic mitochondrial membrane potential changes, some of which are hallmarks of neurodegenerative and mood disorders. Released mtDNA can mediate inflammatory responses observed in many neurological and mood disorders by driving the expression of inflammatory cytokines and the interferon response system. The current understanding of the role of mtDNA release in affective mood disorders and neurodegenerative diseases will be discussed.
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Affiliation(s)
| | - Phillip D. Rivera
- Department of Chemistry and Biology, Hope College, Holland, MI 49423, USA;
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26
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Ouyang H, Huang M, Xu Y, Yao Q, Wu X, Zhou D. Reduced Cell-Free Mitochondrial DNA Levels Were Induced by Antipsychotics Treatment in First-Episode Patients With Schizophrenia. Front Psychiatry 2021; 12:652314. [PMID: 34305669 PMCID: PMC8292716 DOI: 10.3389/fpsyt.2021.652314] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 06/07/2021] [Indexed: 11/13/2022] Open
Abstract
Cell-free mitochondrial DNA (cf-mtDNA) is a damage-associated molecular pattern that boosts the release of cytokines and induces the immune response of the body; therefore, it is closely related to mental diseases. This study aims to evaluate a potential link between cf-mtDNA and clinical progression in first-episode patients with schizophrenia. In this study, plasma cf-mtDNA levels in 34 first-episode patients with schizophrenia before and after 8 weeks of antipsychotic treatment were examined. In addition, the clinical progression of first-episode schizophrenia was assessed using the Positive and Negative Syndrome Scale (PANSS). The copy number changes in the plasma cf-mtDNA (Δcf-mtDNA) were significantly correlated with changes in the PANSS scale scores (ΔPANSS) in first-episode patients with schizophrenia (ΔPANSS total score, P = 0.002; ΔPANSS positive score, P = 0.01). Plasma cf-mtDNA may represent a relevant tool in the future to assist in the assessment of clinical progression in first-episode patients with schizophrenia.
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Affiliation(s)
- Houxian Ouyang
- Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, China.,Department of Laboratory Diagnostics, Ningbo Kangning Hospital, Ningbo, China
| | - Minfang Huang
- Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, China.,Department of Pharmacology, Ningbo Kangning Hospital, Ningbo, China
| | - Yongming Xu
- Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, China
| | - Qin Yao
- Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, China.,Ningbo Key Laboratory of Sleep Medicine, Ningbo, China
| | - Xiangping Wu
- Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, China
| | - Dongsheng Zhou
- Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, China.,Ningbo Key Laboratory of Sleep Medicine, Ningbo, China
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27
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Yang L, Youngblood H, Wu C, Zhang Q. Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation. Transl Neurodegener 2020; 9:19. [PMID: 32475349 PMCID: PMC7262767 DOI: 10.1186/s40035-020-00197-z] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 05/06/2020] [Indexed: 12/18/2022] Open
Abstract
Mitochondrial dysfunction plays a central role in the formation of neuroinflammation and oxidative stress, which are important factors contributing to the development of brain disease. Ample evidence suggests mitochondria are a promising target for neuroprotection. Recently, methods targeting mitochondria have been considered as potential approaches for treatment of brain disease through the inhibition of inflammation and oxidative injury. This review will discuss two widely studied approaches for the improvement of brain mitochondrial respiration, methylene blue (MB) and photobiomodulation (PBM). MB is a widely studied drug with potential beneficial effects in animal models of brain disease, as well as limited human studies. Similarly, PBM is a non-invasive treatment that promotes energy production and reduces both oxidative stress and inflammation, and has garnered increasing attention in recent years. MB and PBM have similar beneficial effects on mitochondrial function, oxidative damage, inflammation, and subsequent behavioral symptoms. However, the mechanisms underlying the energy enhancing, antioxidant, and anti-inflammatory effects of MB and PBM differ. This review will focus on mitochondrial dysfunction in several different brain diseases and the pathological improvements following MB and PBM treatment.
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Affiliation(s)
- Luodan Yang
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA
| | - Hannah Youngblood
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA
| | - Chongyun Wu
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA
| | - Quanguang Zhang
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.
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28
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Czarny P, Wigner P, Strycharz J, Swiderska E, Synowiec E, Szatkowska M, Sliwinska A, Talarowska M, Szemraj J, Su KP, Maes M, Sliwinski T, Galecki P. Mitochondrial DNA copy number, damage, repair and degradation in depressive disorder. World J Biol Psychiatry 2020; 21:91-101. [PMID: 31081430 DOI: 10.1080/15622975.2019.1588993] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Objectives: We aimed to explore mitochondrial DNA (mtDNA) copy number, damage, repair and degradation in peripheral blood mononuclear cells (PBMCs) of patients with depression and to compare the results with healthy subjects.Methods: Total genomic DNA was isolated from PBMCs of 25 depressed and 60 healthy subjects before, immediately after, and 3 h after the exposure to H2O2. Evaluation of mtDNA copy number was performed using real-time PCR and 2-ΔCt methods. Semi-long run real-time PCR was used to estimate the number of mtDNA lesions.Results: Baseline mtDNA copy number did not differ in cells of healthy and depressed subjects; however, it was negatively correlated with the severity of the episode. After a 10-min challenge with hydrogen peroxide (H2O2), depressed patients' PBMCs exhibited slower changes of the copy number, indicating a lower efficiency of mtDNA degradation compared to controls. Moreover, a significantly higher number of mtDNA lesions was found in depressed patients at the baseline as well as at other experimental time points. mtDNA lesions were also elevated in depressed patient cells immediately after H2O2 exposure. Induction of oxidative stress had no significant influence on the cells of controls.Conclusions: We are the first to show that impairment in repair and degradation of mtDNA may be involved in the pathophysiology of depression.
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Affiliation(s)
- Piotr Czarny
- Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Paulina Wigner
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Justyna Strycharz
- Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Ewa Swiderska
- Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Ewelina Synowiec
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Magdalena Szatkowska
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Agnieszka Sliwinska
- Department of Nucleic Acids Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Monika Talarowska
- Department of Adult Psychiatry, Medical University of Lodz, Lodz, Poland
| | - Janusz Szemraj
- Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Kuan-Pin Su
- Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan
| | - Michael Maes
- School of Medicine, Barwon Health, IMPACT Strategic Research Centre Deakin University, Geelong, Australia.,Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand.,Health Sciences Graduate Program Health Sciences Center, State University of Londrina, Londrina, Brazil
| | - Tomasz Sliwinski
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Piotr Galecki
- Department of Adult Psychiatry, Medical University of Lodz, Lodz, Poland
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Chung JK, Lee SY, Park M, Joo EJ, Kim SA. Investigation of mitochondrial DNA copy number in patients with major depressive disorder. Psychiatry Res 2019; 282:112616. [PMID: 31639552 DOI: 10.1016/j.psychres.2019.112616] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 09/25/2019] [Accepted: 10/13/2019] [Indexed: 12/24/2022]
Abstract
Mitochondrial dysfunction is implicated in the pathophysiology of major depressive disorder (MDD). This dysfunction can be indirectly assessed using the mitochondrial DNA (mtDNA) copy number. A total of 118 patients with MDD and 116 age- and sex-matched control subjects were recruited for this study, and mtDNA copy numbers were measured in peripheral blood cells. This study also examined the potential variables that might impact mtDNA copy number in MDD, including age and clinical features. Additionally, epigenetic control of mtDNA copy number was examined by assessing DNA methylation ratios in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) promoter in nuclear DNA and the displacement loop (D-loop) region of mtDNA. The present results showed that patients with MDD had a higher mtDNA copy number and a decreased DNA methylation status in the PGC1α promoter. mtDNA copy numbers were negatively associated with an age, psychomotor agitation, and somatic symptoms in MDD. These results suggest that the alterations in mitochondrial function and epigenetic change of PGC1α may be relevant to the pathophysiology of MDD.
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Affiliation(s)
- Jae Kyung Chung
- Department of Psychiatry, Eumsung-somang Hospital, Eumsung, Republic of Korea
| | - Soo Young Lee
- Department of Pharmacology, School of Medicine, Eulji University, 77, Gyeryong-ro 771 beon-gil, Jung-gu, Daejeon 34824, Republic of Korea
| | - Mira Park
- Department of Preventive Medicine, School of Medicine, Eulji University, Daejeon, Republic of Korea
| | - Eun-Jeong Joo
- Department of Neuropsychiatry, School of Medicine, Eulji University, Daejeon, Republic of Korea; Department of Neuropsychiatry, Department of Psychiatry, Nowon Eulji Medical Center, Eulji University, 68 Hangeulbiseokro, Nowon-Gu, 01830 Seoul, Republic of Korea.
| | - Soon Ae Kim
- Department of Pharmacology, School of Medicine, Eulji University, 77, Gyeryong-ro 771 beon-gil, Jung-gu, Daejeon 34824, Republic of Korea.
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30
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Czarny P, Bialek K, Ziolkowska S, Strycharz J, Sliwinski T. DNA damage and repair in neuropsychiatric disorders. What do we know and what are the future perspectives? Mutagenesis 2019; 35:79-106. [DOI: 10.1093/mutage/gez035] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 09/27/2019] [Indexed: 12/11/2022] Open
Abstract
AbstractOver the past two decades, extensive research has been done to elucidate the molecular etiology and pathophysiology of neuropsychiatric disorders. In majority of them, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), bipolar disorder (BD), schizophrenia and major depressive disorder, increased oxidative and nitrosative stress was found. This stress is known to induce oxidative damage to biomolecules, including DNA. Accordingly, increased mitochondrial and nuclear DNA, as well as RNA damage, were observed in patients suffering from these diseases. However, recent findings indicate that the patients are characterised by impaired DNA repair pathways, which may suggest that these DNA lesions could be also a result of their insufficient repair. In the current systematic, critical review, we aim to sum up, using available literature, the knowledge about the involvement of nuclear and mitochondrial DNA damage and repair, as well as about damage to RNA in pathoetiology of neuropsychiatric disorders, i.e., AD, PD, ALS, BD, schizophrenia and major depressive disorder, as well as the usefulness of the discussed factors as being diagnostic markers and targets for new therapies. Moreover, we also underline the new directions to which future studies should head to elucidate these phenomena.
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Affiliation(s)
- Piotr Czarny
- Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Katarzyna Bialek
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Sylwia Ziolkowska
- Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Justyna Strycharz
- Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Tomasz Sliwinski
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
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31
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Khedr LH, Nassar NN, Rashed L, El-Denshary ED, Abdel-Tawab AM. TLR4 signaling modulation of PGC1-α mediated mitochondrial biogenesis in the LPS-Chronic mild stress model: Effect of fluoxetine and pentoxiyfylline. Life Sci 2019; 239:116869. [PMID: 31678277 DOI: 10.1016/j.lfs.2019.116869] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 09/10/2019] [Accepted: 09/10/2019] [Indexed: 11/15/2022]
Abstract
AIM The addition of repeated lipopolysaccharide (LPS) to chronic mild stress was recently proposed in our lab as an alternative model of depression, highlighting the possible interaction between stress and immune-inflammatory pathways in predisposing depression. Given that CMS-induced depressive behavior was previously related to impaired hippocampal energy metabolism and mitochondrial dysfunction, our current study aimed to investigate the interplay between toll-like receptor 4 (TLR4) signaling and peroxisome proliferator-activated receptor gamma coactivators-1-alpha (PGC1-α) as a physiological regulator of energy metabolism and mitochondrial biogenesis in the combined LPS/CMS model. MAIN METHODS Male Wistar rats were exposed to either LPS (50 μg/kg i.p.) over 2 weeks, CMS protocol for 4 weeks or LPS over 2 weeks followed by 4 weeks of CMS (LPS/CMS). Three additional groups of rats were exposed to LPS/CMS protocol and treated with either pentoxifylline (PTX), fluoxetine (FLX) or a combination of both. Rats were examined for behavioral, neurochemical, gene expression and mitochondrial ultra-structural changes. KEY FINDINGS LPS/CMS increased the expression of TLR4 and its downstream players; MyD88, NFκB and TNF-α along with an escalation in hippocampal-energy metabolism and p-AMPK. Simultaneously LPS/CMS attenuated the expression of PGC1-α/NRF1/Tfam and mt-DNA. The antidepressant (AD) 'FLX', the TNF-α inhibitor 'PTX' and their combination ameliorated the LPS/CMS-induced changes. Interestingly, all the aforementioned changes induced by the LPS/CMS combined model were significantly less than those induced by CMS alone. SIGNIFICANCE Blocking the TLR4/NFκB signaling enhanced the activation of the PGC1-α/NRF1/Tfam and mt-DNA content independent on the activation of the energy-sensing kinase AMPK.
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Affiliation(s)
- L H Khedr
- Departmment of Pharmacology, Faculty of Pharmacy, Misr International University, Cairo, Egypt.
| | - N N Nassar
- Department of Pharmacology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Laila Rashed
- Department of Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - E D El-Denshary
- Department of Pharmacology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - A M Abdel-Tawab
- Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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32
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Sharma S, Akundi RS. Mitochondria: A Connecting Link in the Major Depressive Disorder Jigsaw. Curr Neuropharmacol 2019; 17:550-562. [PMID: 29512466 PMCID: PMC6712299 DOI: 10.2174/1570159x16666180302120322] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 02/02/2018] [Accepted: 02/27/2018] [Indexed: 12/19/2022] Open
Abstract
Background Depression is a widespread phenomenon with varying degrees of pathology in different patients. Various hypotheses have been proposed for the cause and continuance of depression. Some of these include, but not limited to, the monoamine hypothesis, the neuroendocrine hypothesis, and the more recent epigenetic and inflammatory hypotheses. Objective In this article, we review all the above hypotheses with a focus on the role of mitochondria as the connecting link. Oxidative stress, respiratory activity, mitochondrial dynamics and metabolism are some of the mitochondria-dependent factors which are affected during depression. We also propose exogenous ATP as a contributing factor to depression. Result Literature review shows that pro-inflammatory markers are elevated in depressive individuals. The cause for elevated levels of cytokines in depression is not completely understood. We propose exogenous ATP activates purinergic receptors which in turn increase the levels of various pro-inflammatory factors in the pathophysiology of depression. Conclusion Mitochondria are integral to the function of neurons and undergo dysfunction in major depressive disorder patients. This dysfunction is reflected in all the various hypotheses that have been proposed for depression. Among the newer targets identified, which also involve mitochondria, includes the role of exogenous ATP. The diversity of purinergic receptors, and their differential expression among various individuals in the population, due to genetic and environmental (prenatal) influences, may influence the susceptibility and severity of depression. Identifying specific receptors involved and using patient-specific purinergic receptor antagonist may be an appropriate therapeutic course in the future.
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Affiliation(s)
- Shilpa Sharma
- Neuroinflammation Research Lab, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
| | - Ravi S Akundi
- Neuroinflammation Research Lab, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
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Chen J, Vitetta L. Mitochondria could be a potential key mediator linking the intestinal microbiota to depression. J Cell Biochem 2019; 121:17-24. [PMID: 31385365 DOI: 10.1002/jcb.29311] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 07/15/2019] [Indexed: 12/11/2022]
Abstract
The intestinal microbiota has been reported to affect depression, a common mental condition with severe health-related consequences. However, what mediates the effect of the intestinal microbiota on depression has not been well elucidated. We summarize the roles of the mitochondria in eliciting beneficial effects on the gut microbiota to ameliorate symptoms of depression. It is well known that mitochondria play a key role in depression. An important pathogenic factor, namely inflammatory response, may adversely impact mitochondrial functionality to maintain cellular homeostasis. Dysfunction of mitochondria not only affects neuronal function but also reduces neuron cell numbers. We posit that the intestinal microbiota could affect neuronal mitochondrial function through short-chain fatty acids such as butyrate. Brain inflammatory processes could also be affected through the modulation of gut permeability and blood lipopolysaccharide levels. Aberrant mitochondria functionality coupled to adverse cellular homeostasis could be a key mediator for the effect of the intestinal microbiota on the progression of depression.
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Affiliation(s)
| | - Luis Vitetta
- Medlab Clinical Ltd, Sydney, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
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34
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Kim Y, Vadodaria KC, Lenkei Z, Kato T, Gage FH, Marchetto MC, Santos R. Mitochondria, Metabolism, and Redox Mechanisms in Psychiatric Disorders. Antioxid Redox Signal 2019; 31:275-317. [PMID: 30585734 PMCID: PMC6602118 DOI: 10.1089/ars.2018.7606] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 12/21/2018] [Accepted: 12/23/2018] [Indexed: 12/17/2022]
Abstract
Significance: Our current knowledge of the pathophysiology and molecular mechanisms causing psychiatric disorders is modest, but genetic susceptibility and environmental factors are central to the etiology of these conditions. Autism, schizophrenia, bipolar disorder and major depressive disorder show genetic gene risk overlap and share symptoms and metabolic comorbidities. The identification of such common features may provide insights into the development of these disorders. Recent Advances: Multiple pieces of evidence suggest that brain energy metabolism, mitochondrial functions and redox balance are impaired to various degrees in psychiatric disorders. Since mitochondrial metabolism and redox signaling can integrate genetic and environmental environmental factors affecting the brain, it is possible that they are implicated in the etiology and progression of psychiatric disorders. Critical Issue: Evidence for direct links between cellular mitochondrial dysfunction and disease features are missing. Future Directions: A better understanding of the mitochondrial biology and its intracellular connections to the nuclear genome, the endoplasmic reticulum and signaling pathways, as well as its role in intercellular communication in the organism, is still needed. This review focuses on the findings that implicate mitochondrial dysfunction, the resultant metabolic changes and oxidative stress as important etiological factors in the context of psychiatric disorders. We also propose a model where specific pathophysiologies of psychiatric disorders depend on circuit-specific impairments of mitochondrial dysfunction and redox signaling at specific developmental stages.
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Affiliation(s)
- Yeni Kim
- Department of Child and Adolescent Psychiatry, National Center for Mental Health, Seoul, South Korea
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California
| | - Krishna C. Vadodaria
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California
| | - Zsolt Lenkei
- Laboratory of Dynamic of Neuronal Structure in Health and Disease, Institute of Psychiatry and Neuroscience of Paris (UMR_S1266 INSERM, University Paris Descartes), Paris, France
| | - Tadafumi Kato
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Japan
| | - Fred H. Gage
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California
| | - Maria C. Marchetto
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California
| | - Renata Santos
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California
- Laboratory of Dynamic of Neuronal Structure in Health and Disease, Institute of Psychiatry and Neuroscience of Paris (UMR_S1266 INSERM, University Paris Descartes), Paris, France
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35
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Ryan KM, Patterson I, McLoughlin DM. Peroxisome proliferator-activated receptor gamma co-activator-1 alpha in depression and the response to electroconvulsive therapy. Psychol Med 2019; 49:1859-1868. [PMID: 30191781 DOI: 10.1017/s0033291718002556] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), termed the 'master regulator of mitochondrial biogenesis', has been implicated in stress and resilience to stress-induced depressive-like behaviours in animal models. However, there has been no study conducted to date to examine PGC-1α levels in patients with depression or in response to antidepressant treatment. Our aim was to assess PGC-1α mRNA levels in blood from healthy controls and patients with depression pre-/post-electroconvulsive therapy (ECT), and to examine the relationship between blood PGC-1α mRNA levels and clinical symptoms and outcomes with ECT. METHODS Whole blood PGC-1α mRNA levels were analysed in samples from 67 patients with a major depressive episode and 70 healthy controls, and in patient samples following a course of ECT using quantitative real-time polymerase chain reaction (qRT-PCR). Exploratory subgroup correlational analyses were carried out to determine the relationship between PGC-1α and mood scores. RESULTS PGC-1α levels were lower in patients with depression compared with healthy controls (p = 0.03). This lower level was predominantly accounted for by patients with psychotic unipolar depression (p = 0.004). ECT did not alter PGC-1α levels in the depressed group as a whole, though exploratory analyses revealed a significant increase in PGC-1α in patients with psychotic unipolar depression post-ECT (p = 0.045). We found no relationship between PGC-1α mRNA levels and depression severity or the clinical response to ECT. CONCLUSIONS PGC-1α may represent a novel therapeutic target for the treatment of depression, and be a common link between various pathophysiological processes implicated in depression.
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Affiliation(s)
- Karen M Ryan
- Trinity College Institute of Neuroscience, Trinity College Dublin,Dublin,Ireland
| | - Ian Patterson
- Trinity College Institute of Neuroscience, Trinity College Dublin,Dublin,Ireland
| | - Declan M McLoughlin
- Trinity College Institute of Neuroscience, Trinity College Dublin,Dublin,Ireland
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36
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Antidepressant and Anxiolytic Effects of Geraniol in Mice: The Possible Role of Oxidative Stress and Apoptosis. IRANIAN RED CRESCENT MEDICAL JOURNAL 2019. [DOI: 10.5812/ircmj.91593] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Allen J, Romay-Tallon R, Brymer KJ, Caruncho HJ, Kalynchuk LE. Mitochondria and Mood: Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression. Front Neurosci 2018; 12:386. [PMID: 29928190 PMCID: PMC5997778 DOI: 10.3389/fnins.2018.00386] [Citation(s) in RCA: 232] [Impact Index Per Article: 33.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 05/22/2018] [Indexed: 12/15/2022] Open
Abstract
Human and animal studies suggest an intriguing link between mitochondrial diseases and depression. Although depression has historically been linked to alterations in monoaminergic pharmacology and adult hippocampal neurogenesis, new data increasingly implicate broader forms of dampened plasticity, including plasticity within the cell. Mitochondria are the cellular powerhouse of eukaryotic cells, and they also regulate brain function through oxidative stress and apoptosis. In this paper, we make the case that mitochondrial dysfunction could play an important role in the pathophysiology of depression. Alterations in mitochondrial functions such as oxidative phosphorylation (OXPHOS) and membrane polarity, which increase oxidative stress and apoptosis, may precede the development of depressive symptoms. However, the data in relation to antidepressant drug effects are contradictory: some studies reveal they have no effect on mitochondrial function or even potentiate dysfunction, whereas other studies show more beneficial effects. Overall, the data suggest an intriguing link between mitochondrial function and depression that warrants further investigation. Mitochondria could be targeted in the development of novel antidepressant drugs, and specific forms of mitochondrial dysfunction could be identified as biomarkers to personalize treatment and aid in early diagnosis by differentiating between disorders with overlapping symptoms.
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Affiliation(s)
- Josh Allen
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | | | - Kyle J Brymer
- Department of Psychology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Hector J Caruncho
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Lisa E Kalynchuk
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
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Lindqvist D, Wolkowitz OM, Picard M, Ohlsson L, Bersani FS, Fernström J, Westrin Å, Hough CM, Lin J, Reus VI, Epel ES, Mellon SH. Circulating cell-free mitochondrial DNA, but not leukocyte mitochondrial DNA copy number, is elevated in major depressive disorder. Neuropsychopharmacology 2018; 43:1557-1564. [PMID: 29453441 PMCID: PMC5983469 DOI: 10.1038/s41386-017-0001-9] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 11/23/2017] [Accepted: 12/21/2017] [Indexed: 01/07/2023]
Abstract
Major depressive disorder (MDD) has been linked to mitochondrial defects, which could manifest in mitochondrial DNA (mtDNA) polymorphisms or mutations. Additionally, copy number of mtDNA (mtDNA-cn) can be quantified in peripheral blood mononuclear cells (PBMC)s, indirectly reflecting cellular energetics, or in the circulating cell-free mtDNA (ccf-mtDNA) levels, which may reflect a fraction of the mitochondrial genome released during cellular stress. Few studies have examined ccf-mtDNA in MDD, and no studies have tested its relationship with intracellular mtDNA-cn or with antidepressant treatment response. Here, mtDNA levels were quantified in parallel from: (i) PBMCs and (ii) cell-free plasma of 50 unmedicated MDD subjects and 55 controls, in parallel with PBMC telomere length (TL) and antioxidant enzyme glutathione peroxidase (GpX) activity. MtDNA measures were repeated in 19 MDD subjects after 8 weeks of open-label SSRI treatment. In analyses adjusted for age, sex, BMI, and smoking, MDD subjects had significantly elevated levels of ccf-mtDNA (F = 20.6, p = 0.00002). PBMC mtDNA-cn did not differ between groups (p > 0.4). In preliminary analyses, we found that changes in ccf-mtDNA with SSRI treatment differed between SSRI responders and non-responders (F = 6.47, p = 0.02), with the non-responders showing an increase in ccf-mtDNA and responders not changing. Baseline ccf-mtDNA was positively correlated with GpX (r = 0.32, p = 0.001), and PBMC mtDNA correlated positively with PBMC TL (r = 0.38, p = 0.0001). These data suggest that plasma ccf-mtDNA and PBMC mtDNA-cn reflect different cellular processes and that the former may be more reflective of certain aspects of MDD pathophysiology and of the response to SSRI antidepressants.
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Affiliation(s)
- Daniel Lindqvist
- Faculty of Medicine, Department of Clinical Sciences, Psychiatry, Lund University, Lund, Sweden. .,Department of Psychiatry, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA, USA. .,Psychiatric Clinic, Lund, Division of Psychiatry, Lund, Sweden.
| | - Owen M. Wolkowitz
- 0000 0001 2297 6811grid.266102.1Department of Psychiatry, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA USA
| | - Martin Picard
- 0000 0001 2285 2675grid.239585.0Division of Behavioral Medicine, Department of Psychiatry, Columbia University Medical Center, New York, NY USA ,0000 0001 2285 2675grid.239585.0Department of Neurology and Columbia Translational Neuroscience Initiative, Columbia University Medical Center, New York, NY USA ,0000 0001 2285 2675grid.239585.0Columbia Aging Center, Columbia University Medical Center, New York, NY USA
| | - Lars Ohlsson
- 0000 0000 9961 9487grid.32995.34Department of Biomedical Science, Malmö University, Malmö, Sweden
| | - Francesco S. Bersani
- 0000 0001 2297 6811grid.266102.1Department of Psychiatry, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA USA ,grid.7841.aDepartment of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy
| | - Johan Fernström
- 0000 0001 0930 2361grid.4514.4Faculty of Medicine, Department of Clinical Sciences, Psychiatry, Lund University, Lund, Sweden ,Psychiatric Clinic, Lund, Division of Psychiatry, Lund, Sweden
| | - Åsa Westrin
- 0000 0001 0930 2361grid.4514.4Faculty of Medicine, Department of Clinical Sciences, Psychiatry, Lund University, Lund, Sweden ,Psychiatric Clinic, Lund, Division of Psychiatry, Lund, Sweden
| | - Christina M. Hough
- 0000 0001 2297 6811grid.266102.1Department of Psychiatry, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA USA ,0000 0000 9632 6718grid.19006.3ePresent Address: Department of Psychology, University of California, Los Angeles (UCLA), Los Angeles, CA USA
| | - Jue Lin
- 0000 0001 2297 6811grid.266102.1Department of Biochemistry and Biophysics, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA USA
| | - Victor I. Reus
- 0000 0001 2297 6811grid.266102.1Department of Psychiatry, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA USA
| | - Elissa S. Epel
- 0000 0001 2297 6811grid.266102.1Department of Psychiatry, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA USA
| | - Synthia H. Mellon
- 0000 0001 2297 6811grid.266102.1Department of OB/GYN and Reproductive Sciences, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA USA
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Wang D, Li Z, Liu W, Zhou J, Ma X, Tang J, Chen X. Differential mitochondrial DNA copy number in three mood states of bipolar disorder. BMC Psychiatry 2018; 18:149. [PMID: 29801445 PMCID: PMC5970444 DOI: 10.1186/s12888-018-1717-8] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 05/02/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Accumulating evidences indicated that mitochondrial abnormalities were associated with bipolar disorder. As a sensitive index of mitochondrial function and biogenesis, Mitochondrial DNA copy number (mtDNAcn) may be involved in the pathophysiology of bipolar disorder. METHODS Leukocyte relative mtDNAcn was measured by quantitative polymerase chain reaction in subjects with BD (n = 131) in manic, depressive, and euthymic symptoms. Thirty-four healthy individuals were used as comparison control. BD clinical symptomatology was evaluated by Young Mania Rating Scale (YMRS), Hamilton Depression Scale (HAM-D), Clinical Global Impression-Bipolar Disorder-Severity of Illness Scale (CGI-BD-S), and the Positive and Negative Syndrome Scale (PANSS). RESULTS Compared to healthy controls, BD patients with manic and depressive symptoms presented significantly decreased mtDNAcn levels (p-value = 0.009 and 0.041, respectively). No significant differences were detected in mtDNAcn between euthymic patients and healthy controls. The mtDNAcn was negatively correlated with the number of relapses in manic patients (β = - 0.341, p = 0.044). CONCLUSIONS Our study described the first evidence of (1) a significant decline of mtDNAcn in manic BD patients, (2) a similar decreased level of mtDNAcn between manic and depressed BD patients, (3) a negative correlation of mtDNAcn with number of relapses in patients suffering from manic states. Alterations of mtDNAcn in manic and depressed patients, which may reflect disturbances of energy metabolism, supported the role of mitochondrial abnormalities in the pathophysiology of BD.
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Affiliation(s)
- Dong Wang
- 0000 0004 1803 0208grid.452708.cDepartment of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan China ,0000 0004 1803 0208grid.452708.cMental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, Hunan China
| | - Zongchang Li
- 0000 0004 1803 0208grid.452708.cDepartment of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan China ,0000 0001 0379 7164grid.216417.7Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Weiqing Liu
- grid.414902.aDepartment of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan China
| | - Jun Zhou
- 0000 0004 1803 0208grid.452708.cDepartment of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan China ,0000 0004 1803 0208grid.452708.cMental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, Hunan China
| | - Xiaoqian Ma
- 0000 0004 1803 0208grid.452708.cDepartment of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan China ,0000 0004 1803 0208grid.452708.cMental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, Hunan China
| | - Jinsong Tang
- Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China. .,National Clinical Research Center on Mental Disorders, Changsha, Hunan, China. .,National Technology Institute on Mental Disorders, Changsha, Hunan, China. .,Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, Hunan, China.
| | - Xiaogang Chen
- Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China. .,National Clinical Research Center on Mental Disorders, Changsha, Hunan, China. .,National Technology Institute on Mental Disorders, Changsha, Hunan, China. .,Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, Hunan, China.
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Tymofiyeva O, Blom EH, Ho TC, Connolly CG, Lindqvist D, Wolkowitz OM, Lin J, LeWinn KZ, Sacchet MD, Han LKM, Yuan JP, Bhandari SP, Xu D, Yang TT. High levels of mitochondrial DNA are associated with adolescent brain structural hypoconnectivity and increased anxiety but not depression. J Affect Disord 2018; 232:283-290. [PMID: 29500956 PMCID: PMC5864120 DOI: 10.1016/j.jad.2018.02.024] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 01/19/2018] [Accepted: 02/15/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Adolescent anxiety and depression are highly prevalent psychiatric disorders that are associated with altered molecular and neurocircuit profiles. Recently, increased mitochondrial DNA copy number (mtDNA-cn) has been found to be associated with several psychopathologies in adults, especially anxiety and depression. The associations between mtDNA-cn and anxiety and depression have not, however, been investigated in adolescents. Moreover, to date there have been no studies examining associations between mtDNA-cn and brain network alterations in mood disorders in any age group. METHODS The first aim of this study was to compare salivary mtDNA-cn between 49 depressed and/or anxious adolescents and 35 well-matched healthy controls. The second aim of this study was to identify neural correlates of mtDNA-cn derived from diffusion tensor imaging (DTI) and tractography, in the full sample of adolescents. RESULTS There were no diagnosis-specific alterations in mtDNA-cn. However, there was a positive correlation between mtDNA-cn and levels of anxiety, but not depression, in the full sample of adolescents. A subnetwork of connections largely corresponding to the left fronto-occipital fasciculus had significantly lower fractional anisotropy (FA) values in adolescents with higher than median mtDNA-cn. LIMITATIONS Undifferentiated analysis of free and intracellular mtDNA and use of DTI-based tractography represent this study's limitations. CONCLUSIONS The results of this study help elucidate the relationships between clinical symptoms, molecular changes, and neurocircuitry alterations in adolescents with and without anxiety and depression, and they suggest that increased mtDNA-cn is associated both with increased anxiety symptoms and with decreased fronto-occipital structural connectivity in this population.
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Affiliation(s)
- Olga Tymofiyeva
- Department of Radiology & Biomedical Imaging, University of California San Francisco, United States.
| | - Eva Henje Blom
- Department of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco, United States,Department of Clinical Sciences/ Child- and Adolescent Psychiatry, Umeå University, Umeå, Sweden
| | - Tiffany C. Ho
- Department of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco, United States,Department of Psychology, Stanford University, United States
| | - Colm G. Connolly
- Department of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco, United States
| | - Daniel Lindqvist
- Department of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco, United States,Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Psychiatry, Sweden
| | - Owen M. Wolkowitz
- Department of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco, United States
| | - Jue Lin
- Department of Biochemistry and Biophysics, University of California San Francisco, United States
| | - Kaja Z. LeWinn
- Department of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco, United States
| | - Matthew D. Sacchet
- Department of Psychiatry and Behavioral Sciences, Stanford University, United States
| | - Laura K. M. Han
- Department of Psychiatry, Amsterdam Neuroscience, VU University Medical Center, GGZ inGeest, Amsterdam Public Health research institute, Amsterdam, The Netherlands
| | - Justin P. Yuan
- Department of Radiology & Biomedical Imaging, University of California San Francisco, United States
| | - Sarina P. Bhandari
- Department of Radiology & Biomedical Imaging, University of California San Francisco, United States
| | - Duan Xu
- Department of Radiology & Biomedical Imaging, University of California San Francisco, United States
| | - Tony T. Yang
- Department of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco, United States
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Depression, telomeres and mitochondrial DNA: between- and within-person associations from a 10-year longitudinal study. Mol Psychiatry 2018; 23:850-857. [PMID: 28348385 DOI: 10.1038/mp.2017.48] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 12/21/2016] [Accepted: 01/17/2017] [Indexed: 12/16/2022]
Abstract
Alterations in cellular aging, indexed by leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn), might partly account for the increased health risks in persons with depression. Although some studies indeed found cross-sectional associations of depression with LTL and mtDNAcn, the longitudinal associations remain unclear. This 10-year longitudinal study examined between- and within-person associations of depressive symptoms with LTL and mtDNAcn in a large community sample. Data are from years 15, 20 and 25 follow-up evaluations in 977 subjects from the Coronary Artery Risk Development in Young Adults study. Depressive symptoms (years 15, 20, 25) were assessed with the Center for Epidemiologic Studies Depression (CES-D) scale; LTL (years 15, 20, 25) and mtDNAcn (years 15, 25) were measured in whole blood by quantitative PCR. With mixed-model analyses, we explored between- and within-person associations between CES-D scores and cellular aging markers. Results showed that high levels of depressive symptomatology throughout the 10-year time span was associated with shorter average LTL over 10 years (B=-4.2; P=0.014) after covarying for age, sex, race and education. However, no within-person association was found between depressive symptoms and LTL at each year (B=-0.8; P=0.548). Further, we found no between-person (B=-0.2; P=0.744) or within-person (B=0.4; P=0.497) associations between depressive symptomatology and mtDNAcn. Our results provide evidence for a long-term, between-person relationship of depressive symptoms with LTL, rather than a dynamic and direct within-person relationship. In this study, we found no evidence for an association between depressive symptoms and mtDNAcn.
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Guyatt AL, Burrows K, Guthrie PAI, Ring S, McArdle W, Day INM, Ascione R, Lawlor DA, Gaunt TR, Rodriguez S. Cardiometabolic phenotypes and mitochondrial DNA copy number in two cohorts of UK women. Mitochondrion 2018; 39:9-19. [PMID: 28818596 PMCID: PMC5832987 DOI: 10.1016/j.mito.2017.08.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 06/06/2017] [Accepted: 08/10/2017] [Indexed: 12/14/2022]
Abstract
The mitochondrial genome is present at variable copy number between individuals. Mitochondria are vulnerable to oxidative stress, and their dysfunction may be associated with cardiovascular disease. The association of mitochondrial DNA copy number with cardiometabolic risk factors (lipids, glycaemic traits, inflammatory markers, anthropometry and blood pressure) was assessed in two independent cohorts of European origin women, one in whom outcomes were measured at mean (SD) age 30 (4.3) years (N=2278) and the second at 69.4 (5.5) years (N=2872). Mitochondrial DNA copy number was assayed by quantitative polymerase chain reaction. Associations were adjusted for smoking, sociodemographic status, laboratory factors and white cell traits. Out of a total of 12 outcomes assessed in both cohorts, mitochondrial DNA copy number showed little or no association with the majority (point estimates were close to zero and nearly all p-values were >0.01). The strongest evidence was for an inverse association in the older cohort with insulin (standardised beta [95%CI]: -0.06, [-0.098, -0.022], p=0.002), but this association did not replicate in the younger cohort. Our findings do not provide support for variation in mitochondrial DNA copy number having an important impact on cardio-metabolic risk factors in European origin women.
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Affiliation(s)
- Anna L Guyatt
- MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
| | - Kimberley Burrows
- MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
| | - Philip A I Guthrie
- School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
| | - Sue Ring
- MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
| | - Wendy McArdle
- MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
| | - Ian N M Day
- School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
| | - Raimondo Ascione
- Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK
| | - Debbie A Lawlor
- MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
| | - Tom R Gaunt
- MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
| | - Santiago Rodriguez
- MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
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Bustamante AC, Armstrong DL, Uddin M. Epigenetic profiles associated with major depression in the human brain. Psychiatry Res 2018; 260:439-442. [PMID: 29272728 DOI: 10.1016/j.psychres.2017.12.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 11/01/2017] [Accepted: 12/06/2017] [Indexed: 01/25/2023]
Abstract
We conducted an epigenome-wide association study of Major Depressive Disorder (MDD) in brain-derived DNA using two analytic approaches. DNA methylation data (GSE41826) was used in differential methylation (DM) analyses controlling for age, sex, suicide status, and post-mortem interval; and in weighted gene co-methylation network analyses (WGCNA) in probes mapping to transcription start sites. No probes in the DM analysis survived FDR correction. Nominally significant DM probes were enriched in synaptic function-related genes. WGCNA revealed one module correlated with MDD, enriched in genes associated with mitochondrial function. DM and WGCNA both showed enrichment of genes involved in transcription and DNA binding.
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Affiliation(s)
- Angela C Bustamante
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Don L Armstrong
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Champaign, IL, USA
| | - Monica Uddin
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Champaign, IL, USA; Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, IL, USA.
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Anderson G. Linking the biological underpinnings of depression: Role of mitochondria interactions with melatonin, inflammation, sirtuins, tryptophan catabolites, DNA repair and oxidative and nitrosative stress, with consequences for classification and cognition. Prog Neuropsychopharmacol Biol Psychiatry 2018; 80:255-266. [PMID: 28433458 DOI: 10.1016/j.pnpbp.2017.04.022] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 04/01/2017] [Indexed: 01/08/2023]
Abstract
The pathophysiological underpinnings of neuroprogressive processes in recurrent major depressive disorder (rMDD) are reviewed. A wide array of biochemical processes underlie MDD presentations and their shift to a recurrent, neuroprogressive course, including: increased immune-inflammation, tryptophan catabolites (TRYCATs), mitochondrial dysfunction, aryl hydrocarbonn receptor activation, and oxidative and nitrosative stress (O&NS), as well as decreased sirtuins and melatonergic pathway activity. These biochemical changes may have their roots in central, systemic and/or peripheral sites, including in the gut, as well as in developmental processes, such as prenatal stressors and breastfeeding consequences. Consequently, conceptualizations of MDD have dramatically moved from simple psychological and central biochemical models, such as lowered brain serotonin, to a conceptualization that incorporates whole body processes over a lifespan developmental timescale. However, important hubs are proposed, including the gut-brain axis, and mitochondrial functioning, which may provide achievable common treatment targets despite considerable inter-individual variability in biochemical changes. This provides a more realistic model of the complexity of MDD and the pathophysiological processes that underpin the shift to rMDD and consequent cognitive deficits. Such accumulating data on the pathophysiological processes underpinning MDD highlights the need in psychiatry to shift to a classification system that is based on biochemical processes, rather than subjective phenomenology.
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45
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The interplay between inflammation, oxidative stress, DNA damage, DNA repair and mitochondrial dysfunction in depression. Prog Neuropsychopharmacol Biol Psychiatry 2018; 80:309-321. [PMID: 28669580 DOI: 10.1016/j.pnpbp.2017.06.036] [Citation(s) in RCA: 207] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 06/05/2017] [Accepted: 06/29/2017] [Indexed: 12/13/2022]
Abstract
A growing body of evidence suggests that inflammation, mitochondrial dysfunction and oxidant-antioxidant imbalance may play a significant role in the development and progression of depression. Elevated levels of reactive oxygen and nitrogen species - a result of oxidant-antioxidant imbalance - may lead to increased damage of biomolecules, including DNA. This was confirmed in depressed patients in a research study conducted by our team and other scientists. 8-oxoguanine - a marker of oxidative DNA damage - was found in the patients' lymphocytes, urine and serum. These results were confirmed using a comet assay on lymphocytes. Furthermore, it was shown that the patients' cells repaired peroxide-induced DNA damage less efficiently than controls' cells and that some single nucleotide polymorphisms (SNP) of the genes involved in oxidative DNA damage repair may modulate the risk of depression. Lastly, less efficient DNA damage repair observed in the patients can be, at least partly, attributed to the presence of specific SNP variants, as it was revealed through a genotype-phenotype analysis. In conclusion, the available literature shows that both oxidative stress and less efficient DNA damage repair may lead to increased DNA damage in depressed patients. A similar mechanism may result in mitochondrial dysfunction, which is observed in depression.
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46
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Black CN, Bot M, Scheffer PG, Snieder H, Penninx BWJH. Uric acid in major depressive and anxiety disorders. J Affect Disord 2018; 225:684-690. [PMID: 28917195 DOI: 10.1016/j.jad.2017.09.003] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 07/17/2017] [Accepted: 09/02/2017] [Indexed: 01/01/2023]
Abstract
BACKGROUND Uric acid has neuroprotective effects, owing to its antioxidant properties. Lowered antioxidant capacity, causing increased oxidative stress, may be involved in affective disorders and might be altered by antidepressants. This study investigated the association of plasma uric acid, the greatest contributor to blood antioxidant capacity, with major depressive disorder (MDD) and anxiety disorders. METHODS Data were from the Netherlands Study of Depression and Anxiety including patients with current (N = 1648), remitted (N = 609) MDD and/or anxiety disorders (of which N = 710 antidepressant users) and 618 controls. Diagnoses were established with the Composite International Diagnostic Interview. Symptom severity was assessed with the Inventory of Depressive Symptoms-Self Report, Beck Anxiety Inventory and Fear Questionnaire. Uric acid was measured in plasma. Analyses were adjusted for sociodemographic, health and lifestyle variables. RESULTS Plasma uric acid adjusted mean levels were lower in current MDD and/or anxiety disorder(s) (289μmol/l) compared to remitted disorders (298μmol/l, p < .001) and controls (299μmol/l, p < .001; Cohen's d .10). This finding was independent of antidepressant use. Depressive (β-.05, p = .0012), anxiety (β-.04, p = .009) and phobic (β-.03, p = .036) symptom severity, and symptom duration (β-.04, p = .009) were negatively associated with uric acid. LIMITATIONS Limitations include the lack of data on dietary intake which could be a potential confounding factor. From these cross-sectional findings, the association between uric acid and psychopathology cannot be inferred to be causal. CONCLUSION This large scale study finds plasma uric acid levels are lower in current, but not remitted, MDD and/or anxiety disorders, according to a dose-response gradient. This suggests the involvement of decreased antioxidant status in affective disorders, and points to their potential as an avenue for treatment.
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Affiliation(s)
- Catherine N Black
- Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands.
| | - Mariska Bot
- Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands
| | - Peter G Scheffer
- Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
| | - Harold Snieder
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Brenda W J H Penninx
- Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands
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Wang Q, Dwivedi Y. Transcriptional profiling of mitochondria associated genes in prefrontal cortex of subjects with major depressive disorder. World J Biol Psychiatry 2017; 18:592-603. [PMID: 27269743 PMCID: PMC5389940 DOI: 10.1080/15622975.2016.1197423] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Recent evidences suggest that mitochondrial dysfunction maybe involved in the pathophysiology of major depressive disorder (MDD); however, the role of mitochondrial genes in this disorder has not been studied systematically. In the present study, we profiled expression of mitochondrial genes in dorsolateral prefrontal cortex (dlPFC) of MDD and non-psychiatric control subjects. METHODS Human mitochondrial RT2 profile PCR array plates were used to examine differentially expressed genes in dlPFC of 11 MDD and 11 control subjects. Differentially expressed genes were validated independently by qRT-PCR. Biological relevance of differentially expressed genes was analysed by gene ontology (GO) and ingenuity pathways analysis (IPA). RESULTS We found that 16 genes were differentially expressed in the MDD group compared with control group. Among them, three genes were downregulated and 13 genes upregulated. None of these genes were affected by confounding variables, such as age, post-mortem interval, brain pH, and antidepressant toxicology. Seven differentially expressed genes were successfully validated in MDD subjects. GO and IPA analyses identified several new regulatory networks associated with mitochondrial dysfunctions in MDD. CONCLUSIONS Our findings suggest abnormal mitochondrial systems in the brain of MDD subjects which could be involved in the etiopathogenesis of this disorder.
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Affiliation(s)
- Qingzhong Wang
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Yogesh Dwivedi
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
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48
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Social Origins of Developmental Risk for Mental and Physical Illness. J Neurosci 2017; 37:10783-10791. [PMID: 29118206 DOI: 10.1523/jneurosci.1822-17.2017] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2017] [Revised: 10/03/2017] [Accepted: 10/10/2017] [Indexed: 12/19/2022] Open
Abstract
Adversity in early childhood exerts an enduring impact on mental and physical health, academic achievement, lifetime productivity, and the probability of interfacing with the criminal justice system. More science is needed to understand how the brain is affected by early life stress (ELS), which produces excessive activation of stress response systems broadly throughout the child's body (toxic stress). Our research examines the importance of sex, timing and type of stress exposure, and critical periods for intervention in various brain systems across species. Neglect (the absence of sensitive and responsive caregiving) or disrupted interaction with offspring induces robust, lasting consequences in mice, monkeys, and humans. Complementary assessment of internalizing disorders and brain imaging in children suggests that early adversity can interfere with white matter development in key brain regions, which may increase risk for emotional difficulties in the long term. Neural circuits that are most plastic during ELS exposure in monkeys sustain the greatest change in gene expression, offering a mechanism whereby stress timing might lead to markedly different long-term behaviors. Rodent models reveal that disrupted maternal-infant interactions yield metabolic and behavioral outcomes often differing by sex. Moreover, ELS may further accelerate or delay critical periods of development, which reflect GABA circuit maturation, BDNF, and circadian Clock genes. Such factors are associated with several mental disorders and may contribute to a premature closure of plastic windows for intervention following ELS. Together, complementary cross-species studies are elucidating principles of adaptation to adversity in early childhood with molecular, cellular, and whole organism resolution.
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49
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Dannenmann B, Lehle S, Lorscheid S, Huber SM, Essmann F, Schulze-Osthoff K. Simultaneous quantification of DNA damage and mitochondrial copy number by long-run DNA-damage quantification (LORD-Q). Oncotarget 2017; 8:112417-112425. [PMID: 29348835 PMCID: PMC5762520 DOI: 10.18632/oncotarget.20112] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 07/26/2017] [Indexed: 11/29/2022] Open
Abstract
DNA damage and changes in the mitochondrial DNA content have been implicated in ageing and cancer development. To prevent genomic instability and tumorigenesis, cells must maintain the integrity of their nuclear and mitochondrial DNA. Advances in the research of DNA damage protection and genomic stability, however, also depend on the availability of techniques that can reliably quantify alterations of mitochondrial DNA copy numbers and DNA lesions in an accurate high-throughput manner. Unfortunately, no such method has been established yet. Here, we describe the high-sensitivity long-run real-time PCR technique for DNA-damage quantification (LORD-Q) and its suitability to simultaneously measure DNA damage rates and mitochondrial DNA copy numbers in cultured cells and tissue samples. Using the LORD-Q multiplex assay, we exemplarily show that the mitochondrial DNA content does not directly affect DNA damage susceptibility, but influences the efficacy of certain anticancer drugs. Hence, LORD-Q provides a fast and precise method to assess DNA lesions, DNA repair and mtDNA replication as well as their role in a variety of pathological settings.
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Affiliation(s)
- Benjamin Dannenmann
- Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany
| | - Simon Lehle
- Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany
| | - Sebastian Lorscheid
- Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany
| | - Stephan M Huber
- Department of Radiation Oncology, University of Tübingen, 72076 Tübingen, Germany
| | - Frank Essmann
- Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany
| | - Klaus Schulze-Osthoff
- Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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50
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Shin J, Kim KC, Lee DC, Lee HR, Shim JY. Association between Salivary Mitochondrial DNA Copy Number and Chronic Fatigue according to Combined Symptoms in Korean Adults. Korean J Fam Med 2017; 38:206-212. [PMID: 28775810 PMCID: PMC5541168 DOI: 10.4082/kjfm.2017.38.4.206] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 07/13/2016] [Accepted: 08/02/2016] [Indexed: 11/24/2022] Open
Abstract
Background We examined the association between salivary mitochondrial DNA (mtDNA) copy number and chronic fatigue combined with depression and insomnia. Methods This cross-sectional study included 58 healthy adults with moderate to severe fatigue (Brief Fatigue Inventory [BFI] ≥4) for longer than 6 months. Subjects were classified as those without combined symptoms, with either depression (Beck Depression Inventory [BDI] ≥13) or insomnia (Pittsburgh Sleep Quality Index [PSQI] ≥5), or with both depression and insomnia. Salivary mtDNA copy number was measured by real-time quantitative polymerase chain reaction. The association was evaluated using a general linear model. Results About 76% of participants had either depression or insomnia as additional symptoms. These subjects were predominately female, drank more alcohol, and exercised less than those without combined symptoms (P<0.05). The group with both depression and insomnia exhibited significantly higher BFI and lower mtDNA copy number than those without combined symptoms (P<0.05). After adjusting for confounding factors, significant negative associations between mtDNA copy number and usual fatigue were found in the group without combined symptoms, whereas the negative associations in the group with combined symptoms were attenuated. BDI and PSQI were not associated with mtDNA copy number. Conclusion Chronic fatigue is negatively associated with salivary mtDNA copy number. Salivary mtDNA copy number may be a biological marker of fatigue with or without combined symptoms, indicating that a separate approach is necessary.
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Affiliation(s)
- Jinyoung Shin
- Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kyong Chol Kim
- Department of Family Medicine, Miz Medi Hospital, Seoul, Korea
| | - Duk Chul Lee
- Department of Family Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Ree Lee
- Department of Family Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Jae Yong Shim
- Department of Family Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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