Yuki Kageyama1, Takaoki Kasahara2, Masaki Kato3, Shiho Sakai3, Yasuhiko Deguchi4, Munehide Tani5, Kenji Kuroda6, Kotaro Hattori7, Sumiko Yoshida8, Yuichi Goto7, Toshihiko Kinoshita3, Koki Inoue4, Tadafumi Kato9. 1. Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan; Department of Neuropsychiatry, Osaka City University, Graduate School of Medicine, Osaka, Japan. 2. Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan. 3. Department of Neuropsychiatry, Kansai Medical University, Osaka, Japan. 4. Department of Neuropsychiatry, Osaka City University, Graduate School of Medicine, Osaka, Japan. 5. Tani Mental Clinic, Osaka, Japan. 6. Department of Psychiatry, Hannan Hospital, Osaka, Japan. 7. Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan. 8. Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Psychiatry, National Center of Neurology and Psychiatry Hospital, Tokyo, Japan. 9. Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan. Electronic address: kato@brain.riken.jp.
Abstract
BACKGROUND: Although inflammatory cytokines are established biomarkers of mood disorders, their molecular mechanism is not known. We hypothesized that circulating mitochondrial DNA (mtDNA) contributes to inflammation and could be used as biomarkers. We investigated if circulating mtDNA level is associated with inflammatory cytokines and can be used as a biomarker of mood disorders. METHODS: Plasma mtDNA concentration was measured with real-time quantitative PCR targeting two regions of the mtDNA and plasma levels of four cytokines (GM-CSF, IL-2, IL-4, and IL-6) were measured with a multiplex immunoassay method in 109 patients with major depressive disorder (MDD). The most significantly correlated cytokine was verified with an enzyme-linked immunosorbent assay (ELISA). The data from 28 patients with bipolar disorder (BD), 17 patients with schizophrenia (SZ), and 29 healthy controls were compared. RESULTS: MtDNA levels showed a nominal positive correlation with GM-CSF, IL-2 and IL-4 in patients with MDD. The most significant correlation with IL-4 (ρ = 0.38, P < 0.00005) was verified with an ELISA (ρ = 0.19, P = 0.049). Unexpectedly, patients with MDD and BD showed significantly lower plasma mtDNA levels than controls. MtDNA levels were lower in the depressive state than in the euthymic state in patients with MDD. Patients with depression, bipolar disorder, and schizophrenia did not show significantly higher levels of these four cytokines than controls. LIMITATIONS: There is a possibility that the patients in this study are different from previous studies in which increased cytokine levels were reported. MtDNA levels should be measured in patients showing elevated plasma cytokine levels. A larger sample is required to generalize the results. CONCLUSIONS: The present findings coincide with our hypothesis that circulating mtDNA contributes to the inflammation in MDD. Further studies are needed to conclude whether plasma mtDNA would be a biomarker of mood disorders.
BACKGROUND: Although inflammatory cytokines are established biomarkers of mood disorders, their molecular mechanism is not known. We hypothesized that circulating mitochondrial DNA (mtDNA) contributes to inflammation and could be used as biomarkers. We investigated if circulating mtDNA level is associated with inflammatory cytokines and can be used as a biomarker of mood disorders. METHODS: Plasma mtDNA concentration was measured with real-time quantitative PCR targeting two regions of the mtDNA and plasma levels of four cytokines (GM-CSF, IL-2, IL-4, and IL-6) were measured with a multiplex immunoassay method in 109 patients with major depressive disorder (MDD). The most significantly correlated cytokine was verified with an enzyme-linked immunosorbent assay (ELISA). The data from 28 patients with bipolar disorder (BD), 17 patients with schizophrenia (SZ), and 29 healthy controls were compared. RESULTS: MtDNA levels showed a nominal positive correlation with GM-CSF, IL-2 and IL-4 in patients with MDD. The most significant correlation with IL-4 (ρ = 0.38, P < 0.00005) was verified with an ELISA (ρ = 0.19, P = 0.049). Unexpectedly, patients with MDD and BD showed significantly lower plasma mtDNA levels than controls. MtDNA levels were lower in the depressive state than in the euthymic state in patients with MDD. Patients with depression, bipolar disorder, and schizophrenia did not show significantly higher levels of these four cytokines than controls. LIMITATIONS: There is a possibility that the patients in this study are different from previous studies in which increased cytokine levels were reported. MtDNA levels should be measured in patients showing elevated plasma cytokine levels. A larger sample is required to generalize the results. CONCLUSIONS: The present findings coincide with our hypothesis that circulating mtDNA contributes to the inflammation in MDD. Further studies are needed to conclude whether plasma mtDNA would be a biomarker of mood disorders.
Authors: Laura K M Han; Josine E Verhoeven; Audrey R Tyrka; Brenda W J H Penninx; Owen M Wolkowitz; Kristoffer N T Månsson; Daniel Lindqvist; Marco P Boks; Dóra Révész; Synthia H Mellon; Martin Picard Journal: Psychoneuroendocrinology Date: 2019-04-05 Impact factor: 4.905
Authors: Giselli Scaini; Brittany L Mason; Alexandre P Diaz; Manish K Jha; Jair C Soares; Madhukar H Trivedi; João Quevedo Journal: Mol Psychiatry Date: 2021-10-14 Impact factor: 15.992
Authors: Yann L C Becker; Bhargavi Duvvuri; Paul R Fortin; Christian Lood; Eric Boilard Journal: Nat Rev Rheumatol Date: 2022-09-29 Impact factor: 32.286
Authors: Kathryn L Humphreys; Lucinda M Sisk; Erika M Manczak; Jue Lin; Ian H Gotlib Journal: J Am Acad Child Adolesc Psychiatry Date: 2019-10-16 Impact factor: 8.829