title: Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics.
abstract: 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.
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Eguchi
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kawahara
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan; Faculty of Pharmacy, Keio University, Minato, Tokyo 105-8512, Japan.
authors.forename: Nanami
authors.initials: N
authors.lastname: Hasegawa
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Faculty of Pharmacy, Keio University, Minato, Tokyo 105-8512, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Funakoshi-Tago
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Tanoue
authors.affiliation: Faculty of Pharmacy, Keio University, Minato, Tokyo 105-8512, Japan.
authors.forename: Hiroomi
authors.initials: H
authors.lastname: Tamura
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan; Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan. Electronic address: yamauchi-j@ncchd.go.jp.
authors.forename: Junji
authors.initials: J
authors.lastname: Yamauchi
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D018834:Chaperonin 60 / Q000235:genetics* / Q000378:metabolism; D002522:Chlorocebus aethiops; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018834:Chaperonin 60; C060293:HSPD1 protein, human; D024101:Mitochondrial Proteins; D011993:Recombinant Fusion Proteins
keywords: Dynamics; Fission and fusion cycle; HLD4; HSPD1; Mitochondria