Departments of Psychiatry and Family Medicine, Kaiser Permanente, San Jose, CA, USA; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, USA; Bradley/Hasbro Children's Research Center, E. P. Bradley Hospital, East Providence, RI, USA.
Psychoneuroendocrinology. 2020 Jun;116:104632. doi: 10.1016/j.psyneuen.2020.104632. Epub 2020 Feb 20.
Glucocorticoid receptor gene (NR3C1) promoter methylation influences cellular expression of the glucocorticoid receptor and is a proposed mechanism by which early life stress impacts neuroendocrine function. Mitochondria are sensitive and responsive to neuroendocrine stress signaling through the glucocorticoid receptor, and recent evidence with this sample and others shows that mitochondrial DNA copy number (mtDNAcn) is increased in adults with a history of early stress. No prior work has examined the role of NR3C1 methylation in the association between early life stress and mtDNAcn alterations.
Adult participants (n = 290) completed diagnostic interviews and questionnaires characterizing early stress and lifetime psychiatric symptoms. Medical conditions, active substance abuse, and prescription medications other than oral contraceptives were exclusionary. Subjects with a history of lifetime bipolar, obsessive-compulsive, or psychotic disorders were excluded; individuals with other forms of major psychopathology were included. Whole blood mtDNAcn was measured using qPCR; NR3C1 methylation was measured via pyrosequencing. Multiple regression and bootstrapping procedures tested NR3C1 methylation as a mediator of effects of early stress on mtDNAcn.
The positive association between early adversity and mtDNAcn (p = .02) was mediated by negative associations of early adversity with NR3C1 methylation (p = .02) and NR3C1 methylation with mtDNAcn (p < .001). The indirect effect involving early adversity, NR3C1 methylation, and mtDNAcn was significant (95 % CI [.002, .030]).
NR3C1 methylation significantly mediates the association between early stress and mtDNAcn, suggesting that glucocorticoid receptor signaling may be a mechanistic pathway underlying mtDNAcn alterations of interest for future longitudinal work.
糖皮质激素受体基因（NR3C1）启动子甲基化影响糖皮质激素受体的细胞表达，是早期生活压力影响神经内分泌功能的一种提出的机制。线粒体对神经内分泌应激信号通过糖皮质激素受体敏感且有反应，并且这个样本和其他样本的最新证据表明，有早期压力史的成年人中线粒体 DNA 拷贝数（mtDNAcn）增加。以前没有研究检查 NR3C1 甲基化在早期生活压力和 mtDNAcn 改变之间的关联中的作用。
成年参与者（n = 290）完成了诊断访谈和问卷调查，这些问卷描述了早期压力和终生精神症状。有医疗条件、主动滥用药物和除口服避孕药以外的处方药物的人被排除在外。有终生双相、强迫症或精神病病史的人被排除在外；有其他形式的主要精神病理学的人被包括在内。使用 qPCR 测量全血 mtDNAcn；通过焦磷酸测序测量 NR3C1 甲基化。多元回归和自举程序测试了 NR3C1 甲基化作为早期压力对 mtDNAcn 的影响的中介。
早期逆境与 mtDNAcn 之间的正相关（p =.02）是由早期逆境与 NR3C1 甲基化（p =.02）和 NR3C1 甲基化与 mtDNAcn（p <.001）之间的负相关介导的。涉及早期逆境、NR3C1 甲基化和 mtDNAcn 的间接效应是显著的（95 % CI [.002，.030]）。
NR3C1 甲基化显著介导了早期压力与 mtDNAcn 之间的关联，这表明糖皮质激素受体信号可能是 mtDNAcn 改变的潜在机制途径，这对未来的纵向工作很重要。
