Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts

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 (<i>WDR45</i>), showing iron accum...

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Autores principales:	Hye Eun Lee, Min Kyo Jung, Seul Gi Noh, Hye Bin Choi, Se hyun Chae, Jae Hyeok Lee, Ji Young Mun
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	iron overload WDR45 lipid metabolism mitochondria lysosome autophagy Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/01f2a931d60945dc815d7fd30176f3bc
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spelling	oai:doaj.org-article:01f2a931d60945dc815d7fd30176f3bc2021-11-11T17:07:30ZIron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts10.3390/ijms2221116501422-00671661-6596https://doaj.org/article/01f2a931d60945dc815d7fd30176f3bc2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11650https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Iron 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 (<i>WDR45</i>), 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 <i>WDR45</i> 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.Hye Eun LeeMin Kyo JungSeul Gi NohHye Bin ChoiSe hyun ChaeJae Hyeok LeeJi Young MunMDPI AGarticleiron overloadWDR45lipid metabolismmitochondrialysosomeautophagyBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11650, p 11650 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	iron overload WDR45 lipid metabolism mitochondria lysosome autophagy Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	iron overload WDR45 lipid metabolism mitochondria lysosome autophagy Biology (General) QH301-705.5 Chemistry QD1-999 Hye Eun Lee Min Kyo Jung Seul Gi Noh Hye Bin Choi Se hyun Chae Jae Hyeok Lee Ji Young Mun Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts
description	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 (<i>WDR45</i>), 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 <i>WDR45</i> 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.
format	article
author	Hye Eun Lee Min Kyo Jung Seul Gi Noh Hye Bin Choi Se hyun Chae Jae Hyeok Lee Ji Young Mun
author_facet	Hye Eun Lee Min Kyo Jung Seul Gi Noh Hye Bin Choi Se hyun Chae Jae Hyeok Lee Ji Young Mun
author_sort	Hye Eun Lee
title	Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts
title_short	Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts
title_full	Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts
title_fullStr	Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts
title_full_unstemmed	Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts
title_sort	iron accumulation and changes in cellular organelles in wdr45 mutant fibroblasts
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/01f2a931d60945dc815d7fd30176f3bc
work_keys_str_mv	AT hyeeunlee ironaccumulationandchangesincellularorganellesinwdr45mutantfibroblasts AT minkyojung ironaccumulationandchangesincellularorganellesinwdr45mutantfibroblasts AT seulginoh ironaccumulationandchangesincellularorganellesinwdr45mutantfibroblasts AT hyebinchoi ironaccumulationandchangesincellularorganellesinwdr45mutantfibroblasts AT sehyunchae ironaccumulationandchangesincellularorganellesinwdr45mutantfibroblasts AT jaehyeoklee ironaccumulationandchangesincellularorganellesinwdr45mutantfibroblasts AT jiyoungmun ironaccumulationandchangesincellularorganellesinwdr45mutantfibroblasts
_version_	1718432158839734272

Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts

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