Neural Circuit Research Group, Korea Brain Research Institute, Daegu 41068, Korea.
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Korea.
Int J Mol Sci. 2021 Oct 28;22(21):11650. doi: 10.3390/ijms222111650.
Iron overload in the brain, defined as excess stores of iron, is known to be associated with neurological disorders. In neurodegeneration accompanied by brain iron accumulation, we reported a specific point mutation, c.974-1G>A in WD Repeat Domain 45 (), showing iron accumulation in the brain, and autophagy defects in the fibroblasts. In this study, we investigated whether fibroblasts with mutated WDR45 accumulated iron, and other effects on cellular organelles. We first identified the main location of iron accumulation in the mutant fibroblasts and then investigated the effects of this accumulation on cellular organelles, including lipid droplets, mitochondria and lysosomes. Ultrastructure analysis using transmission electron microscopy (TEM) and confocal microscopy showed structural changes in the organelles. Increased numbers of lipid droplets, fragmented mitochondria and increased numbers of lysosomal vesicles with functional disorder due to deficiency were observed. Based on correlative light and electron microscopy (CLEM) findings, most of the iron accumulation was noted in the lysosomal vesicles. These changes were associated with defects in autophagy and defective protein and organelle turnover. Gene expression profiling analysis also showed remarkable changes in lipid metabolism, mitochondrial function, and autophagy-related genes. These data suggested that functional and structural changes resulted in impaired lipid metabolism, mitochondrial disorder, and unbalanced autophagy fluxes, caused by iron overload.
脑内铁过载是指铁的蓄积过多，已知其与神经紊乱相关。在伴有脑铁蓄积的神经退行性疾病中，我们报道了 WD 重复结构域 45 （）的一个特定点突变 c.974-1G>A，其在成纤维细胞中表现为脑内铁蓄积和自噬缺陷。在本研究中，我们调查了突变型 WDR45 成纤维细胞是否蓄积铁以及对其他细胞细胞器的影响。我们首先确定了突变型成纤维细胞中铁蓄积的主要位置，然后研究了这种蓄积对细胞器的影响，包括脂滴、线粒体和溶酶体。透射电子显微镜（TEM）和共聚焦显微镜的超微结构分析显示出细胞器的结构变化。由于 缺乏，观察到脂滴数量增加、线粒体碎片化和溶酶体囊泡数量增加，且功能紊乱。基于相关的光镜和电镜（CLEM）发现，大多数铁蓄积在溶酶体囊泡中。这些变化与自噬缺陷和蛋白质及细胞器周转缺陷有关。基因表达谱分析也显示脂质代谢、线粒体功能和自噬相关基因的显著变化。这些数据表明，铁过载导致的功能和结构变化引起了脂质代谢、线粒体紊乱和不平衡的自噬流受损。
