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Mol. Cells

Published online January 10, 2023

© The Korean Society for Molecular and Cellular Biology

RUNX1 Upregulation Causes Mitochondrial Dysfunction via Regulating the PI3K-Akt Pathway in iPSC from Patients with Down Syndrome

Yanna Liu1,4 , Yuehua Zhang1,4 , Zhaorui Ren1,2 , Fanyi Zeng1,2,3,* , and Jingbin Yan1,2,*

1Shanghai Children’s Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, China, 2NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology, Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China, 3Department of Histoembryology, Genetics & Development, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, 4These authors contributed equally to this work.

Correspondence to : yanjb@shchildren.com.cn (JY); fzeng@vip.163.com (FZ)

Received: June 6, 2022; Revised: September 30, 2022; Accepted: October 3, 2022

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

Down syndrome (DS) is the most common autosomal aneuploidy caused by trisomy of chromosome 21. Previous studies demonstrated that DS affected mitochondrial functions, which may be associated with the abnormal development of the nervous system in patients with DS. Runt-related transcription factor 1 (RUNX1) is an encoding gene located on chromosome 21. It has been reported that RUNX1 may affect cell apoptosis via the mitochondrial pathway. The present study investigated whether RUNX1 plays a critical role in mitochondrial dysfunction in DS and explored the mechanism by which RUNX1 affects mitochondrial functions. Expression of RUNX1 was detected in induced pluripotent stem cells of patients with DS (DS-iPSCs) and normal iPSCs (N-iPSCs), and the mitochondrial functions were investigated in the current study. Subsequently, RUNX1 was overexpressed in N-iPSCs and inhibited in DS-iPSCs. The mitochondrial functions were investigated thoroughly, including reactive oxygen species levels, mitochondrial membrane potential, ATP content and lysosomal activity. Finally, RNA-sequencing was used to explore the global expression pattern. It was observed that the expression levels of RUNX1 in DS-iPSCs were significantly higher than those in normal controls. Impaired mitochondrial functions were observed in DS-iPSCs. Of note, overexpression of RUNX1 in N-iPSCs resulted in mitochondrial dysfunction, while inhibition of RUNX1 expression could improve the mitochondrial function in DS-iPSCs. Global gene expression analysis indicated that overexpression of RUNX1 may promote the induction of apoptosis in DS-iPSCs by activating the PI3K/Akt signaling pathway. The present findings indicate that abnormal expression of RUNX1 may play a critical role in mitochondrial dysfunction in DS-iPSCs.

Keywords Down syndrome, induced pluripotent stem cells, mitochondrial dysfunction, RUNX1

Article

On-line First

Mol. Cells

Published online January 10, 2023

Copyright © The Korean Society for Molecular and Cellular Biology.

RUNX1 Upregulation Causes Mitochondrial Dysfunction via Regulating the PI3K-Akt Pathway in iPSC from Patients with Down Syndrome

Yanna Liu1,4 , Yuehua Zhang1,4 , Zhaorui Ren1,2 , Fanyi Zeng1,2,3,* , and Jingbin Yan1,2,*

1Shanghai Children’s Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, China, 2NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology, Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China, 3Department of Histoembryology, Genetics & Development, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, 4These authors contributed equally to this work.

Correspondence to:yanjb@shchildren.com.cn (JY); fzeng@vip.163.com (FZ)

Received: June 6, 2022; Revised: September 30, 2022; Accepted: October 3, 2022

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

Down syndrome (DS) is the most common autosomal aneuploidy caused by trisomy of chromosome 21. Previous studies demonstrated that DS affected mitochondrial functions, which may be associated with the abnormal development of the nervous system in patients with DS. Runt-related transcription factor 1 (RUNX1) is an encoding gene located on chromosome 21. It has been reported that RUNX1 may affect cell apoptosis via the mitochondrial pathway. The present study investigated whether RUNX1 plays a critical role in mitochondrial dysfunction in DS and explored the mechanism by which RUNX1 affects mitochondrial functions. Expression of RUNX1 was detected in induced pluripotent stem cells of patients with DS (DS-iPSCs) and normal iPSCs (N-iPSCs), and the mitochondrial functions were investigated in the current study. Subsequently, RUNX1 was overexpressed in N-iPSCs and inhibited in DS-iPSCs. The mitochondrial functions were investigated thoroughly, including reactive oxygen species levels, mitochondrial membrane potential, ATP content and lysosomal activity. Finally, RNA-sequencing was used to explore the global expression pattern. It was observed that the expression levels of RUNX1 in DS-iPSCs were significantly higher than those in normal controls. Impaired mitochondrial functions were observed in DS-iPSCs. Of note, overexpression of RUNX1 in N-iPSCs resulted in mitochondrial dysfunction, while inhibition of RUNX1 expression could improve the mitochondrial function in DS-iPSCs. Global gene expression analysis indicated that overexpression of RUNX1 may promote the induction of apoptosis in DS-iPSCs by activating the PI3K/Akt signaling pathway. The present findings indicate that abnormal expression of RUNX1 may play a critical role in mitochondrial dysfunction in DS-iPSCs.

Keywords: Down syndrome, induced pluripotent stem cells, mitochondrial dysfunction, RUNX1

Mol. Cells
Jan 31, 2023 Vol.46 No.1, pp. 1~67
COVER PICTURE
RNAs form diverse shapes and play multiple functions as central molecules of gene expression. In this special issue on RNA, seven minireviews illustrate how basic concepts and recent RNA biology findings are transformed into new and exciting RNA therapeutics.

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