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首页> 外文期刊>Journal of Molecular Biology >Structure/Function Relations in AIFM1 Variants Associated with Neurodegenerative Disorders
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Structure/Function Relations in AIFM1 Variants Associated with Neurodegenerative Disorders

机译：与神经退行性疾病相关的AIFM1变体中的结构/功能关系。

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摘要

The X-linked AIFM1 gene encodes mitochondrial apoptosis-inducing factor (AIF), an FAD-containing and NADH-specific oxidoreductase critically important for energy metabolism and execution of the caspase-independent cell death pathway. Several recently identified mutations in human AIFM1 lead to neurodegenerative disorders varying in severity and onset time. This study was undertaken to structurally and functionally characterize four pathologic variants of human AIF: V243L, G262S, G308E, and G338E. A strong correlation between the mutational effects on the AIF function and clinical phenotype was observed only for the G308E aberration, drastically damaging both the redox properties of AIF and mitochondrial respiration. In contrast, only minimal or mild changes were detected in the structure/function of AIF V243L and G338E, respectively, indicating that a marked decrease in their cellular expression likely triggers the disease. Alterations in the structure and redox activity of AIF G262S, on the other hand, were more severe than could be predicted based on the clinical phenotype. Together, the results of this and previous studies allow to conclude that the phenotypic variability and severity of the A/FM1-related disorders depend on which AIF feature is predominantly affected (i.e., cellular production level, structure, redox or apoptogenic function) and to what extent. Only a drastic decrease in the expression level or/and redox activity of AIF tends to cause an early and severe neurodegeneration, whereas less pronounced changes in the AIF properties could lead to a broad range of slowly progressive neurological disorders. (C) 2016 Elsevier Ltd. All rights reserved.
机译：X连锁的AIFM1基因编码线粒体凋亡诱导因子（AIF），这是一种含FAD和NADH特异性的氧化还原酶，对于能量代谢和caspase依赖性细胞死亡途径的执行至关重要。最近在人类AIFM1中鉴定出的几种突变会导致神经退行性疾病，其严重程度和发作时间各不相同。进行这项研究是为了在结构和功能上表征人类AIF的四种病理变异：V243L，G262S，G308E和G338E。仅对于G308E像差，观察到了对AIF功能的突变效应与临床表型之间的密切相关性，从而极大地破坏了AIF的氧化还原特性和线粒体呼吸。相反，在AIF V243L和G338E的结构/功能中分别仅检测到最小或轻微的变化，表明它们的细胞表达明显下降可能触发了该疾病。另一方面，AIF G262S的结构和氧化还原活性的变化比根据临床表型所预测的更为严重。总之，本研究和以前的研究结果可以得出结论，与A / FM1相关的疾病的表型变异性和严重性取决于主要影响哪种AIF功能（即，细胞产生水平，结构，氧化还原或凋亡的功能）以及什么程度。仅AIF的表达水平或/和氧化还原活性的急剧下降往往会导致早期和严重的神经退行性变，而AIF性质的不太明显的改变则可能导致广泛的缓慢进行性神经系统疾病。 （C）2016 Elsevier Ltd.保留所有权利。

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