Development, Health and Disease Research Program, University of California, School of Medicine, Irvine, CA, USA; Department of Pediatrics, University of California, School of Medicine, Irvine, CA, USA.
Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Merritt Center, Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY, USA; New York State Psychiatric Institute, New York, NY, USA.
Psychoneuroendocrinology. 2022 Oct;144:105868. doi: 10.1016/j.psyneuen.2022.105868. Epub 2022 Jul 15.
Mitochondria are multifunctional energy-producing and signaling organelles that support life and contribute to stress adaptation. There is a growing understanding of the dynamic relationship between stress exposure and mitochondrial biology; however, the influence of stress on key domains of mitochondrial biology during early-life, particularly the earliest phases of intra-uterine/prenatal period remains largely unknown. Thus, the goal of this study was to examine the impact of fetal exposure to stress (modeled as the biological construct allostatic load) upon mitochondrial biology in early childhood.
In n = 30 children (range: 3.5-6 years, 53% male), we quantified mitochondrial content via citrate synthase (CS) activity and mtDNA copy number (mtDNAcn), and measured mitochondrial bioenergetic capacity via respiratory chain enzyme activities (complexes I (CI), II (CII), and IV (CIV)) in platelet-depleted peripheral blood mononuclear cells (PBMCs). In a cohort of healthy pregnant women, maternal allostatic load was operationalized as a latent variable (sum of z-scores) representing an aggregation of early-, mid- and late-gestation measures of neuroendocrine (cortisol), immune (interleukin-6, C-reactive protein), metabolic (homeostasis model assessment of insulin resistance, free fatty acids), and cardiovascular (aggregate systolic and diastolic blood pressure) systems, as well as an anthropometric indicator (pre-pregnancy body mass index [BMI]).
An interquartile increase in maternal allostatic load during pregnancy was associated with higher mitochondrial content (24% and 15% higher CS and mtDNAcn), and a higher mitochondrial bioenergetic capacity (16%, 23%, and 25% higher CI, CII and CIV enzymatic activities) in child leukocytes. The positive association between maternal allostatic load during pregnancy and child mitochondrial content and bioenergetic capacity remained significant after accounting for the effects of key pre- and post-natal maternal and child covariates (p's < 0.05, except CI p = 0.073).
We report evidence that prenatal biological stress exposure, modeled as allostatic load, was associated with elevated child mitochondrial content and bioenergetic capacity in early childhood. This higher mitochondrial content and bioenergetic capacity (per leukocyte) may reflect increased energetic demands at the immune or organism level, and thus contribute to wear-and-tear and pathophysiology, and/or programmed pro-inflammatory phenotypes. These findings provide potential mechanistic insight into the cellular processes underlying developmental programming, and support the potential role that changes in mitochondrial content and bioenergetic functional capacity may play in altering life-long susceptibility for health and disease.
线粒体是多功能的能量产生和信号细胞器，支持生命并有助于应激适应。人们越来越了解应激暴露与线粒体生物学之间的动态关系；然而，在生命早期，特别是宫内/产前阶段，应激对线粒体生物学关键领域的影响在很大程度上仍然未知。因此，本研究的目的是检查胎儿暴露于应激（建模为适应负荷的生物构建体）对儿童早期线粒体生物学的影响。
在 n = 30 名儿童（年龄范围：3.5-6 岁，53%为男性）中，我们通过柠檬酸合酶 (CS) 活性和线粒体 DNA 拷贝数 (mtDNAcn) 来量化线粒体含量，并通过血小板耗尽的外周血单核细胞 (PBMC) 中的呼吸链酶活性 (复合物 I (CI)、复合物 II (CII) 和复合物 IV (CIV)) 来测量线粒体生物能。在一组健康孕妇中，母体适应负荷被操作化为一个潜在变量（z 分数的总和），代表神经内分泌（皮质醇）、免疫（白细胞介素-6、C 反应蛋白）、代谢（胰岛素抵抗的稳态模型评估、游离脂肪酸）和心血管（收缩压和舒张压总和）系统的早期、中期和晚期妊娠测量指标，以及一个人体测量指标（孕前体重指数 [BMI]）。
妊娠期间母体适应负荷的四分位距增加与儿童白细胞中更高的线粒体含量（CS 和 mtDNAcn 分别增加 24%和 15%）和更高的线粒体生物能（CI、CII 和 CIV 酶活性分别增加 16%、23%和 25%）相关。在校正关键的产前和产后母婴协变量的影响后，妊娠期间母体适应负荷与儿童线粒体含量和生物能之间的正相关仍然显著（p 值均 <0.05，除 CI 的 p 值 = 0.073）。
我们报告的证据表明，产前生物应激暴露，建模为适应负荷，与儿童早期线粒体含量和生物能的增加有关。这种更高的线粒体含量和生物能（每个白细胞）可能反映了免疫或机体水平的能量需求增加，从而导致磨损和病理生理学，以及/或程序化的促炎表型。这些发现为发育编程的细胞过程提供了潜在的机制见解，并支持线粒体含量和生物能功能能力的变化可能在改变终生对健康和疾病的易感性方面发挥的作用。
