Immortalized Parkinson's disease lymphocytes have enhanced mitochondrial respiratory activity.
Immortalized Parkinson's disease lymphocytes have enhanced mitochondrial respiratory activity.
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DOI：
10.1242/dmm.025684
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发表时间：
2016-11-01
影响因子：
4.3
通讯作者：
Fisher PR
中科院分区：
文献类型：
--
作者：
Annesley SJ;Lay ST;De Piazza SW;Sanislav O;Hammersley E;Allan CY;Francione LM;Bui MQ;Chen ZP;Ngoei KR;Tassone F;Kemp BE;Storey E;Evans A;Loesch DZ;Fisher PR
结合对死后帕金森病（PD）大脑的研究，PD的药理学和遗传学模型表明，两个基本的相互作用的细胞过程受损-蛋白质稳态和线粒体呼吸。我们重新研究了线粒体功能障碍在淋巴母细胞中的作用，这些淋巴母细胞分离自特发性PD患者和年龄匹配的对照组。如先前报道的各种PD细胞类型，PD淋巴母细胞产生的活性氧（ROS）显著升高。然而，这并不是由于线粒体呼吸的损害，因为通常假设。相反，基础线粒体呼吸和ATP合成显着升高PD淋巴母细胞。线粒体质量、基因组拷贝数和膜电位不变，但指示性呼吸复合物蛋白的表达也升高。这解释了iPD细胞的实验性非偶联线粒体中每种呼吸复合物的耗氧速率增加。然而，这并不归因于应激和能量敏感蛋白激酶AMPK的活性增加，AMPK是线粒体生物发生和活性的调节剂。iPD和对照细胞之间的呼吸差异足以提供疾病状态的潜在敏感和可靠的生物标志物，不受疾病持续时间（自诊断以来的时间）或临床严重程度的影响。因此，来自对照和PD个体的淋巴母细胞占据两种不同的、准稳定的稳定状态;“正常”和“过度活跃”状态，其特征在于两种不同的代谢率。面对患者老龄化、正在进行的疾病和不断增加的疾病严重程度，患者来源的淋巴母细胞中的“过度活跃”状态的明显稳定性表明早期永久转换为替代代谢稳态。由于其相关的ROS产生增加，“过度活跃”状态可能不会对快速翻转的细胞造成病理，但脑细胞可能会积累长期损伤，最终导致神经退行性变和死后观察到的线粒体功能丧失。淋巴母细胞中的“过度活跃”状态是否是PD或更普遍的神经退行性疾病的特异性生物标志物仍有待确定。编辑选择：培养的帕金森氏病淋巴细胞是代谢过度活跃的，这表明了对这种和潜在的其他神经退行性疾病的潜在细胞病理学和生物标志物的新理解。
In combination with studies of post-mortem Parkinson's disease (PD) brains, pharmacological and genetic models of PD have suggested that two fundamental interacting cellular processes are impaired – proteostasis and mitochondrial respiration. We have re-examined the role of mitochondrial dysfunction in lymphoblasts isolated from individuals with idiopathic PD and an age-matched control group. As previously reported for various PD cell types, the production of reactive oxygen species (ROS) by PD lymphoblasts was significantly elevated. However, this was not due to an impairment of mitochondrial respiration, as is often assumed. Instead, basal mitochondrial respiration and ATP synthesis are dramatically elevated in PD lymphoblasts. The mitochondrial mass, genome copy number and membrane potential were unaltered, but the expression of indicative respiratory complex proteins was also elevated. This explains the increased oxygen consumption rates by each of the respiratory complexes in experimentally uncoupled mitochondria of iPD cells. However, it was not attributable to increased activity of the stress- and energy-sensing protein kinase AMPK, a regulator of mitochondrial biogenesis and activity. The respiratory differences between iPD and control cells were sufficiently dramatic as to provide a potentially sensitive and reliable biomarker of the disease state, unaffected by disease duration (time since diagnosis) or clinical severity. Lymphoblasts from control and PD individuals thus occupy two distinct, quasi-stable steady states; a ‘normal’ and a ‘hyperactive’ state characterized by two different metabolic rates. The apparent stability of the ‘hyperactive’ state in patient-derived lymphoblasts in the face of patient ageing, ongoing disease and mounting disease severity suggests an early, permanent switch to an alternative metabolic steady state. With its associated, elevated ROS production, the ‘hyperactive’ state might not cause pathology to cells that are rapidly turned over, but brain cells might accumulate long-term damage leading ultimately to neurodegeneration and the loss of mitochondrial function observed post-mortem. Whether the ‘hyperactive’ state in lymphoblasts is a biomarker specifically of PD or more generally of neurodegenerative disease remains to be determined. Editors' choice: Cultured Parkinson's disease lymphocytes are metabolically hyperactive, suggesting a new understanding of the underlying cytopathology and biomarkers for this and potentially other neurodegenerative diseases.
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影响因子：
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