Home » Key Scientific Articles » Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics

Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics

Significance Statement

Hereditary hypomyelinating leukodystrophy 4 (HLD4)-associated mutation of mitochondrial heat shock protein HSPD1 causes blunted dynamics of mitochondria in cells and in turn apoptotic cell death. Pelizaeus-Merzbacher disease (PMD) is now known as the prototypic Hereditary hypomyelinating leukodystrophy (HLD1). Next-generation sequencing technique has clarified that Hereditary hypomyelinating leukodystrophy is heterogenous responsible gene-derived disorders. In contrast to positive control (panel A), a cell expressing the HLD4 mutant is in an apoptotic process (panel B).

Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics.-	. Global Medical Discovery

Journal Reference

Miyamoto Y1, Eguchi T2, Kawahara K1, Hasegawa N3, Nakamura K1, Funakoshi-Tago M4, Tanoue A1, Tamura H4, Yamauchi J5. Biochem Biophys Res Commun. 2015 May 6.

Show Affiliations

1Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.

2The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan.

3Department 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.

4Faculty of Pharmacy, Keio University, Minato, Tokyo 105-8512, Japan.

5Department 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: [email protected]

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.

Copyright © 2015 Elsevier Inc. All rights reserved.

Go To Biochemical and Biophysical Research Communications

 

 

 

Global Medical Discovery