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

Agnieszka Zmyslowska,Maciej Borowiec,Dagmara Grot,Joanna Taha,Joseph D Mancias,Hanna Nieznanska,Wojciech Fendler,Aneta Wlodarczyk,Wojciech Mlynarski,Marcin Stanczak,Bartłomiej Pawlik,Miljan Kuljanin,Magdalena Lebiedzińska-Arciszewska,Dominika Michalek,Beata Malachowska,Mariusz R Wieckowski,Piotr Rieske

doi:10.1186/s12964-021-00791-2

Abstract

BackgroundWolfram 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.MethodsWe 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.ResultsProteomic 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.ConclusionsOur results show the functional and morphological secondary mitochondrial damage in patients with WFS.Graphical EQy9i2UA_HE4ksLyXi_ZKvVideo

Highlights

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 endoplasmic reticulum (ER) stress
Wolfram syndrome (WFS) is a rare genetic syndrome inherited in an autosomal recessive manner, which occurs as a result of the presence of pathogenic variants mainly in the WFS1 gene [1, 2]
Wolframin—the product of WFS1 gene—is an integral component of the endoplasmic reticulum (ER) and is expressed in many organs. This protein plays a protective role against ER stress in affected cells and its functional lack in this syndrome results in a number of biological effects and a wide range of clinical symptoms observed in WFS patients [4, 5]

Summary

Introduction

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. Wolframin—the product of WFS1 gene—is an integral component of the endoplasmic reticulum (ER) and is expressed in many organs (e.g., brain, pancreas, liver, heart). This protein plays a protective role against ER stress in affected cells and its functional lack in this syndrome results in a number of biological effects and a wide range of clinical symptoms observed in WFS patients [4, 5]. As a result of the stimulation by requiring inositol factor 1 (IRE1), an unconventional splicing of the mRNA encoding the X-box binding protein 1 (XBP1)

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