Mitochondrial changes within axons in multiple sclerosis
Mitochondrial changes within axons in multiple sclerosis
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DOI：
10.1093/brain/awp046
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发表时间：
2009-05-01
期刊：
影响因子：
14.5
通讯作者：
Turnbull, Douglass M.
中科院分区：
文献类型：
--
作者：
Mahad, Don J.;Ziabreva, Iryna;Turnbull, Douglass M.
多发性硬化症是年轻人非创伤性神经损伤的最常见原因。能量缺乏状态与多发性硬化症中轴突变性（疾病进展的病理相关性）有关。线粒体是最有效的能量生产者，在钙稳态中起着重要作用。我们分别用免疫组织化学和组织化学方法分析了进行性多发性硬化慢性活动性和非活动性病变中线粒体的密度和功能。如前所述，在急性III型和Balos病变中，线粒体呼吸链复合物IV活性降低，尽管脱髓鞘轴突中存在线粒体，淀粉样前体蛋白积聚，其主要位于慢性活动性病变的活动边缘。此外，强的非磷酸化神经丝（SMI 32）的反应性与脱髓鞘轴突内的复合物IV活性和线粒体的显着减少。与轴突损伤相关的复合物IV缺陷可能是由先天免疫的可溶性产物介导的，如慢性病变中复合物IV活性与巨噬细胞/小胶质细胞密度之间的负相关性所示。然而，在慢性多发性硬化病变的非活动区的线粒体呼吸链复合物IV的活性和线粒体质量，判断孔蛋白免疫反应，增加约一半的大（直径2.5米）慢性脱髓鞘轴突相比，在大脑和脊髓中的大有髓轴突。轴突特异性线粒体对接蛋白（syntaphilin）和磷酸化neuroadherent-H在慢性病变中增加。在一定比例的Na/K ATP酶-1阳性脱髓鞘轴突中缺乏复合物IV活性支持轴突功能障碍是神经损伤和疾病进展的一个因素。此外，体外研究表明，复合物IV的抑制增强谷氨酸介导的轴突损伤（淀粉样前体蛋白和SMI 32反应性）。我们的研究结果对多发性硬化进行性阶段的轴突变性和功能障碍具有重要意义。
Multiple sclerosis is the most common cause of non-traumatic neurological impairment in young adults. An energy deficient state has been implicated in the degeneration of axons, the pathological correlate of disease progression, in multiple sclerosis. Mitochondria are the most efficient producers of energy and play an important role in calcium homeostasis. We analysed the density and function of mitochondria using immunohistochemistry and histochemistry, respectively, in chronic active and inactive lesions in progressive multiple sclerosis. As shown before in acute pattern III and Balos lesions, the mitochondrial respiratory chain complex IV activity is reduced despite the presence of mitochondria in demyelinated axons with amyloid precursor protein accumulation, which are predominantly located at the active edge of chronic active lesions. Furthermore, the strong non-phosphorylated neurofilament (SMI32) reactivity was associated with a significant reduction in complex IV activity and mitochondria within demyelinated axons. The complex IV defect associated with axonal injury may be mediated by soluble products of innate immunity, as suggested by an inverse correlation between complex IV activity and macrophage/microglial density in chronic lesions. However, in inactive areas of chronic multiple sclerosis lesions the mitochondrial respiratory chain complex IV activity and mitochondrial mass, judged by porin immunoreactivity, are increased within approximately half of large (2.5 m diameter) chronically demyelinated axons compared with large myelinated axons in the brain and spinal cord. The axon-specific mitochondrial docking protein (syntaphilin) and phosphorylated neurofilament-H were increased in chronic lesions. The lack of complex IV activity in a proportion of Na/K ATPase -1 positive demyelinated axons supports axonal dysfunction as a contributor to neurological impairment and disease progression. Furthermore, in vitro studies show that inhibition of complex IV augments glutamate-mediated axonal injury (amyloid precursor protein and SMI32 reactivity). Our findings have important implications for both axonal degeneration and dysfunction during the progressive stage of multiple sclerosis.