目的:纤维肌痛(FM)的发病机制,以慢性广泛性疼痛和疲劳为特征,仍然是出了名的难以捉摸,阻碍开发疾病改善治疗方法的尝试。线粒体是细胞能量代谢的总部,和他们的故障已被认为有助于FM和慢性疲劳。因此,当前试点研究的目的是,是为了检测FM患者外周血单核细胞(PBMC)的线粒体结构变化,使用透射电子显微镜(TEM)。
方法:为了检测FM中的线粒体结构改变,我们分析了7名患者和7名健康对照的PBMC,使用TEM。患者是从三级医疗中心的专业纤维肌痛诊所招募的。在提供知情同意后,参与者填写了包括广泛疼痛指数(WPI)在内的问卷,症状严重程度评分(SSS),纤维肌痛影响问卷(FIQ),贝克抑郁库存(BDI),和视觉模拟量表(VAS),根据ACR标准验证FM的诊断。随后,抽取血样并收集PBMC进行EM分析.
结果:PBMC的TEM分析显示了几种不同的线粒体cr模式,包括FM患者的cr完全消失。FM患者中具有完整cr形态的线粒体数量减少,完全没有cr的线粒体百分比增加。这些结果与WPI严重程度相关。此外,在FM患者样本中,我们观察到高百分比的细胞含有电子致密聚集体,可能是核糖体聚集体。cr丢失和可能的核糖体聚集是相互关联的,因此可以代表对共同的细胞应激状况的反应。线粒体形态的变化表明线粒体功能障碍,导致低效的氧化磷酸化和ATP生产,代谢和氧化还原紊乱,和增加的活性氧(ROS)水平,可能在FM中起致病作用。
结论:我们描述了FM患者线粒体的新形态变化,包括线粒体cr的损失。虽然这些观察结果不能确定这些变化是致病的还是代表一种附带现象,他们强调了线粒体功能障碍可能在导致FM慢性疼痛和疲劳的级联事件中发挥致病作用的可能性.此外,结果提供了利用线粒体形态变化作为FM客观生物标志物的可能性.进一步了解FM与线粒体生理学功能障碍之间的联系,可能有助于开发新颖的诊断工具以及FM的特定治疗方法,例如改善/加强线粒体功能的方法。
OBJECTIVE: The pathogenesis of fibromyalgia (FM), characterised by chronic widespread pain and fatigue, remains notoriously elusive, hampering attempts to develop disease modifying treatments. Mitochondria are the headquarters of cellular energy metabolism, and their malfunction has been proposed to contribute to both FM and chronic fatigue. Thus, the aim of the current pilot study, was to detect structural changes in mitochondria of peripheral blood mononuclear cells (PBMCs) of FM patients, using transmission electron microscopy (TEM).
METHODS: To detect structural mitochondrial alterations in FM, we analysed PBMCs from seven patients and seven healthy controls, using TEM. Patients were recruited from a specialised Fibromyalgia Clinic at a tertiary medical centre. After providing informed consent, participants completed questionnaires including the widespread pain index (WPI), symptoms severity score (SSS), fibromyalgia impact questionnaire (FIQ), beck depression inventory (BDI), and visual analogue scale (VAS), to verify a diagnosis of FM according to ACR criteria. Subsequently, blood samples were drawn and PBMCs were collected for EM analysis.
RESULTS: TEM analysis of PBMCs showed several distinct mitochondrial cristae patterns, including total loss of cristae in FM patients. The number of mitochondria with intact cristae morphology was reduced in FM patients and the percentage of mitochondria that completely lacked cristae was increased. These results correlated with the WPI severity. Moreover, in the FM patient samples we observed a high percentage of cells containing electron dense aggregates, which are possibly ribosome aggregates. Cristae loss and possible ribosome aggregation were intercorrelated, and thus may represent reactions to a shared cellular stress condition. The changes in mitochondrial morphology suggest that mitochondrial dysfunction, resulting in inefficient oxidative phosphorylation and ATP production, metabolic and redox disorders, and increased reactive oxygen species (ROS) levels, may play a pathogenetic role in FM.
CONCLUSIONS: We describe novel morphological changes in mitochondria of FM patients, including loss of mitochondrial cristae. While these observations cannot determine whether the changes are pathogenetic or represent an epiphenomenon, they highlight the possibility that mitochondrial malfunction may play a causative role in the cascade of events leading to chronic pain and fatigue in FM. Moreover, the results offer the possibility of utilising changes in mitochondrial morphology as an objective biomarker in FM. Further understanding the connection between FM and dysfunction of mitochondria physiology, may assist in developing both novel diagnostic tools as well as specific treatments for FM, such as approaches to improve/strengthen mitochondria function.