Miyamoto Yuki, Eguchi Takahiro, Kawahara Kazuko, Hasegawa Nanami, Nakamura Kazuaki, Funakoshi-Tago Megumi, Tanoue Akito, Tamura Hiroomi, Yamauchi Junji
Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan.
Biochem Biophys Res Commun. 2015 Jul 3;462(3):275-81. doi: 10.1016/j.bbrc.2015.04.132. Epub 2015 May 6.
Myelin-forming glial cells undergo dynamic morphological changes in order to produce mature myelin sheaths with multiple layers. In the central nervous system (CNS), oligodendrocytes differentiate to insulate neuronal axons with myelin sheaths. Myelin sheaths play a key role in homeostasis of the nervous system, but their related disorders lead not only to dismyelination and repeated demyelination but also to severe neuropathies. Hereditary hypomyelinating leukodystrophies (HLDs) are a group of such diseases affecting oligodendrocytes and are often caused by missense mutations of the respective responsible genes. Despite increasing identification of gene mutations through advanced nucleotide sequencing technology, studies on the relationships between gene mutations and their effects on cellular and subcellular aberrance have not followed at the same rapid pace. In this study, we report that an HLD4-associated (Asp-29-to-Gly) mutant of mitochondrial heat shock 60-kDa protein 1 (HSPD1) causes short-length morphologies and increases the numbers of mitochondria due to their aberrant fission and fusion cycles. In experiments using a fluorescent dye probe, this mutation decreases the mitochondrial membrane potential. Also, mitochondria accumulate in perinuclear regions. HLD4-associated HSPD1 mutant blunts mitochondrial dynamics, probably resulting in oligodendrocyte malfunction. This study constitutes a first finding concerning the relationship between disease-associated HSPD1 mutation and mitochondrial dynamics, which may be similar to the relationship between another disease-associated HSPD1 mutation (MitCHAP-60 disease) and aberrant mitochondrial dynamics.
形成髓鞘的神经胶质细胞会经历动态的形态变化，以产生具有多层结构的成熟髓鞘。在中枢神经系统（CNS）中，少突胶质细胞分化并通过髓鞘包裹神经元轴突。髓鞘在神经系统的稳态中起着关键作用，但其相关疾病不仅会导致脱髓鞘和反复的髓鞘脱失，还会引发严重的神经病变。遗传性低髓鞘性脑白质营养不良（HLDs）就是一组影响少突胶质细胞的此类疾病，通常由各自相关基因的错义突变引起。尽管通过先进的核苷酸测序技术对基因突变的鉴定越来越多，但关于基因突变与其对细胞和亚细胞异常影响之间关系的研究却没有跟上同样快速的步伐。在本研究中，我们报告线粒体热休克60 kDa蛋白1（HSPD1）的与HLD4相关的（Asp-29-to-Gly）突变体导致线粒体形态变短，并由于其异常的分裂和融合循环而增加线粒体数量。在使用荧光染料探针的实验中，这种突变降低了线粒体膜电位。此外，线粒体在核周区域积聚。与HLD4相关的HSPD1突变体使线粒体动力学减弱，可能导致少突胶质细胞功能障碍。本研究首次发现了疾病相关的HSPD1突变与线粒体动力学之间的关系，这可能与另一种疾病相关的HSPD1突变（MitCHAP-60疾病）与异常线粒体动力学之间的关系相似。
