Multiomic analysis on human cell model of wolfram syndrome reveals changes in mitochondrial morphology and function

Multiomic analysis on human cell model of wolfram syndrome reveals changes in mitochondrial morphology and function

Abstract Background Wolfram syndrome (WFS) is a rare autosomal recessive syndrome in which diabetes mellitus and neurodegenerative disorders occur as a result of Wolframin deficiency and increased ER stress. In addition, WFS1 deficiency leads to calcium homeostasis disturbances and can change mitoch...

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Autores principales: Agnieszka Zmyslowska, Miljan Kuljanin, Beata Malachowska, Marcin Stanczak, Dominika Michalek, Aneta Wlodarczyk, Dagmara Grot, Joanna Taha, Bartłomiej Pawlik, Magdalena Lebiedzińska-Arciszewska, Hanna Nieznanska, Mariusz R. Wieckowski, Piotr Rieske, Joseph D. Mancias, Maciej Borowiec, Wojciech Mlynarski, Wojciech Fendler
Formato: article
Lenguaje:EN
Publicado: BMC 2021
Materias:
Wolfram syndrome
Proteomics
Transcriptomics
Mitochondria
ER stress
Medicine
R
Cytology
QH573-671
Acceso en línea:https://doaj.org/article/e9ae24e4ded347729d7a31887a6ccfdf
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spelling oai:doaj.org-article:e9ae24e4ded347729d7a31887a6ccfdf2021-11-21T12:13:35ZMultiomic analysis on human cell model of wolfram syndrome reveals changes in mitochondrial morphology and function10.1186/s12964-021-00791-21478-811Xhttps://doaj.org/article/e9ae24e4ded347729d7a31887a6ccfdf2021-11-01T00:00:00Zhttps://doi.org/10.1186/s12964-021-00791-2https://doaj.org/toc/1478-811XAbstract Background Wolfram syndrome (WFS) is a rare autosomal recessive syndrome in which diabetes mellitus and neurodegenerative disorders occur as a result of Wolframin deficiency and increased ER stress. In addition, WFS1 deficiency leads to calcium homeostasis disturbances and can change mitochondrial dynamics. The aim of this study was to evaluate protein levels and changes in gene transcription on human WFS cell model under experimental ER stress. Methods We performed transcriptomic and proteomic analysis on WFS human cell model—skin fibroblasts reprogrammed into induced pluripotent stem (iPS) cells and then into neural stem cells (NSC) with subsequent ER stress induction using tunicamycin (TM). Results were cross-referenced with publicly available RNA sequencing data in hippocampi and hypothalami of mice with WFS1 deficiency. Results Proteomic analysis identified specific signal pathways that differ in NSC WFS cells from healthy ones. Next, detailed analysis of the proteins involved in the mitochondrial function showed the down-regulation of subunits of the respiratory chain complexes in NSC WFS cells, as well as the up-regulation of proteins involved in Krebs cycle and glycolysis when compared to the control cells. Based on pathway enrichment analysis we concluded that in samples from mice hippocampi the mitochondrial protein import machinery and OXPHOS were significantly down-regulated. Conclusions Our results show the functional and morphological secondary mitochondrial damage in patients with WFS. Graphical Abstract Video AbstractAgnieszka ZmyslowskaMiljan KuljaninBeata MalachowskaMarcin StanczakDominika MichalekAneta WlodarczykDagmara GrotJoanna TahaBartłomiej PawlikMagdalena Lebiedzińska-ArciszewskaHanna NieznanskaMariusz R. WieckowskiPiotr RieskeJoseph D. ManciasMaciej BorowiecWojciech MlynarskiWojciech FendlerBMCarticleWolfram syndromeProteomicsTranscriptomicsMitochondriaER stressMedicineRCytologyQH573-671ENCell Communication and Signaling, Vol 19, Iss 1, Pp 1-14 (2021)
institution DOAJ
collection DOAJ
language EN
topic Wolfram syndrome
Proteomics
Transcriptomics
Mitochondria
ER stress
Medicine
R
Cytology
QH573-671
spellingShingle Wolfram syndrome
Proteomics
Transcriptomics
Mitochondria
ER stress
Medicine
R
Cytology
QH573-671
Agnieszka Zmyslowska
Miljan Kuljanin
Beata Malachowska
Marcin Stanczak
Dominika Michalek
Aneta Wlodarczyk
Dagmara Grot
Joanna Taha
Bartłomiej Pawlik
Magdalena Lebiedzińska-Arciszewska
Hanna Nieznanska
Mariusz R. Wieckowski
Piotr Rieske
Joseph D. Mancias
Maciej Borowiec
Wojciech Mlynarski
Wojciech Fendler
Multiomic analysis on human cell model of wolfram syndrome reveals changes in mitochondrial morphology and function
description Abstract Background Wolfram syndrome (WFS) is a rare autosomal recessive syndrome in which diabetes mellitus and neurodegenerative disorders occur as a result of Wolframin deficiency and increased ER stress. In addition, WFS1 deficiency leads to calcium homeostasis disturbances and can change mitochondrial dynamics. The aim of this study was to evaluate protein levels and changes in gene transcription on human WFS cell model under experimental ER stress. Methods We performed transcriptomic and proteomic analysis on WFS human cell model—skin fibroblasts reprogrammed into induced pluripotent stem (iPS) cells and then into neural stem cells (NSC) with subsequent ER stress induction using tunicamycin (TM). Results were cross-referenced with publicly available RNA sequencing data in hippocampi and hypothalami of mice with WFS1 deficiency. Results Proteomic analysis identified specific signal pathways that differ in NSC WFS cells from healthy ones. Next, detailed analysis of the proteins involved in the mitochondrial function showed the down-regulation of subunits of the respiratory chain complexes in NSC WFS cells, as well as the up-regulation of proteins involved in Krebs cycle and glycolysis when compared to the control cells. Based on pathway enrichment analysis we concluded that in samples from mice hippocampi the mitochondrial protein import machinery and OXPHOS were significantly down-regulated. Conclusions Our results show the functional and morphological secondary mitochondrial damage in patients with WFS. Graphical Abstract Video Abstract
format article
author Agnieszka Zmyslowska
Miljan Kuljanin
Beata Malachowska
Marcin Stanczak
Dominika Michalek
Aneta Wlodarczyk
Dagmara Grot
Joanna Taha
Bartłomiej Pawlik
Magdalena Lebiedzińska-Arciszewska
Hanna Nieznanska
Mariusz R. Wieckowski
Piotr Rieske
Joseph D. Mancias
Maciej Borowiec
Wojciech Mlynarski
Wojciech Fendler
author_facet Agnieszka Zmyslowska
Miljan Kuljanin
Beata Malachowska
Marcin Stanczak
Dominika Michalek
Aneta Wlodarczyk
Dagmara Grot
Joanna Taha
Bartłomiej Pawlik
Magdalena Lebiedzińska-Arciszewska
Hanna Nieznanska
Mariusz R. Wieckowski
Piotr Rieske
Joseph D. Mancias
Maciej Borowiec
Wojciech Mlynarski
Wojciech Fendler
author_sort Agnieszka Zmyslowska
title Multiomic analysis on human cell model of wolfram syndrome reveals changes in mitochondrial morphology and function
title_short Multiomic analysis on human cell model of wolfram syndrome reveals changes in mitochondrial morphology and function
title_full Multiomic analysis on human cell model of wolfram syndrome reveals changes in mitochondrial morphology and function
title_fullStr Multiomic analysis on human cell model of wolfram syndrome reveals changes in mitochondrial morphology and function
title_full_unstemmed Multiomic analysis on human cell model of wolfram syndrome reveals changes in mitochondrial morphology and function
title_sort multiomic analysis on human cell model of wolfram syndrome reveals changes in mitochondrial morphology and function
publisher BMC
publishDate 2021
url https://doaj.org/article/e9ae24e4ded347729d7a31887a6ccfdf
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