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

• Published in: Cell communication and signaling Vol. 19; no. 1; pp. 116 - 14
• Main Authors: Zmyslowska, Agnieszka, Kuljanin, Miljan, Malachowska, Beata, Stanczak, Marcin, Michalek, Dominika, Wlodarczyk, Aneta, Grot, Dagmara, Taha, Joanna, Pawlik, Bartłomiej, Lebiedzińska-Arciszewska, Magdalena, Nieznanska, Hanna, Wieckowski, Mariusz R, Rieske, Piotr, Mancias, Joseph D, Borowiec, Maciej, Mlynarski, Wojciech, Fendler, Wojciech
• Format: Journal Article
• Language: English
• Published: England BioMed Central 20.11.2021; BMC
• Subjects: Animals; Calcium homeostasis; Chromatography; Cytology; Diabetes mellitus; Electron transport; Endoplasmic Reticulum Stress - genetics; ER stress; Extracellular matrix; Fibroblasts; Glycolysis; Growth factors; Hippocampus; Homeostasis; Humans; Hypothalamus; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; Kinases; Mass spectrometry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Models, Biological; Morphology; Neural stem cells; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neurodegenerative diseases; Nutrient deficiency; Peptides; Pluripotency; Protein transport; Proteins; Proteomics; Reagents; Scientific imaging; Stem cell transplantation; Stem cells; Transcription; Transcriptomics; Tricarboxylic acid cycle; Tunicamycin; Wolfram syndrome; Wolfram Syndrome - genetics; Wolfram Syndrome - metabolism; Wolfram Syndrome - pathology; United States > US; Germany; ER stress; Mitochondria; Wolfram syndrome; Transcriptomics; Proteomics
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-021-00791-2

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. 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. 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. Our results show the functional and morphological secondary mitochondrial damage in patients with WFS. Video Abstract.