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Title: Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics

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 mitochondrialmore » dynamics, which may be similar to the relationship between another disease-associated HSPD1 mutation (MitCHAP-60 disease) and aberrant mitochondrial dynamics. - Highlights: • The HLD4 mutant of HSPD1 decreases mitochondrial fission frequency. • The HLD4 mutant decreases mitochondrial fusion frequency. • Mitochondria harboring the HLD4 mutant exhibit slow motility. • The HLD4 mutant of HSPD1 decreases mitochondrial membrane potential. • HLD4-related diseases may be due to decreased mitochondrial dynamics.« less
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [1] ;  [4] ;  [1] ;  [4] ;  [1] ;  [3]
  1. Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535 (Japan)
  2. The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639 (Japan)
  3. (Japan)
  4. Faculty of Pharmacy, Keio University, Minato, Tokyo 105-8512 (Japan)
Publication Date:
OSTI Identifier:
22462100
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 462; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CENTRAL NERVOUS SYSTEM; DISEASES; DYES; FLUORESCENCE; GENE MUTATIONS; GENES; HEAT; HOMEOSTASIS; LENGTH; MITOCHONDRIA; MORPHOLOGICAL CHANGES; MORPHOLOGY; MUTANTS; MYELIN; NERVE CELLS; NUCLEOTIDES