Goetzl Edward J, Maecker Holden T, Rosenberg-Hasson Yael, Koran Lorrin M
School of Medicine, University of California San Francisco, San Francisco, CA, United States.
Human Immune Monitoring Center, Microbiology and Immunology, Stanford University Medical Center, Stanford, CA, United States.
Front Toxicol. 2022 Jan 12;3:797496. doi: 10.3389/ftox.2021.797496. eCollection 2021.
The retention of the heavy metal, gadolinium, after a Gadolinium-Based Contrast Agent-assisted MRI may lead to a symptom cluster termed Gadolinium Deposition Disease. Little is known of the disorder's underlying pathophysiology, but a recent study reported abnormally elevated serum levels of pro-inflammatory cytokines compared to normal controls. As a calcium channel blocker in cellular plasma and mitochondrial membranes, gadolinium also interferes with mitochondrial function. We applied to sera from nine Gadolinium Deposition Disease and two Gadolinium Storage Condition patients newly developed methods allowing isolation of plasma neuron-derived extracellular vesicles that contain reproducibly quantifiable levels of mitochondrial proteins of all major classes. Patients' levels of five mitochondrial functional proteins were statistically significantly lower and of two significantly higher than the levels in normal controls. The patterns of differences between study patients and controls for mitochondrial dynamics and mitochondrial proteins encompassing neuronal energy generation, metabolic regulation, ion fluxes, and survival differed from those seen for patients with first episode psychosis and those with Major Depressive Disorder compared to their controls. These findings suggest that mitochondrial dysfunction due to retained gadolinium may play a role in causing Gadolinium Deposition Disease. Larger samples of both GDD and GSC patients are needed to allow not only testing the repeatability of our findings, but also investigation of relationships of specific mitochondrial protein deficiencies or excesses and concurrent cytokine, genetic, or other factors to GDD's neurological and cognitive symptoms. Studies of neuronal mitochondrial proteins as diagnostic markers or indicators of treatment effectiveness are also warranted.
基于钆的造影剂辅助磁共振成像（MRI）后，重金属钆的潴留可能导致一种称为钆沉积病的症状群。人们对该疾病的潜在病理生理学知之甚少，但最近一项研究报告称，与正常对照组相比，促炎细胞因子的血清水平异常升高。作为细胞质膜和线粒体膜中的钙通道阻滞剂，钆还会干扰线粒体功能。我们将新开发的方法应用于9例钆沉积病患者和2例钆储存状态患者的血清，该方法可分离出含有所有主要类别的线粒体蛋白且含量可重复定量的血浆神经元衍生细胞外囊泡。患者的5种线粒体功能蛋白水平在统计学上显著低于正常对照组，2种则显著高于正常对照组。研究患者与对照组在涉及神经元能量产生、代谢调节、离子通量和存活的线粒体动力学和线粒体蛋白方面的差异模式，与首发精神病患者和重度抑郁症患者与其对照组相比的差异模式不同。这些发现表明，钆潴留导致的线粒体功能障碍可能在钆沉积病的发生中起作用。需要更大样本量的钆沉积病和钆储存状态患者，不仅用于检验我们研究结果的可重复性，还用于研究特定线粒体蛋白缺乏或过量与同时存在的细胞因子、基因或其他因素与钆沉积病神经和认知症状之间的关系。对神经元线粒体蛋白作为诊断标志物或治疗效果指标的研究也很有必要。
