Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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RUNX1 Upregulation Causes Mitochondrial Dysfunction via Regulating the PI3K-Akt Pathway in iPSC from Patients with Down Syndrome

  • Yanna Liu (Shanghai Children's Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine) ;
  • Yuehua Zhang (Shanghai Children's Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine) ;
  • Zhaorui Ren (Shanghai Children's Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine) ;
  • Fanyi Zeng (Shanghai Children's Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine) ;
  • Jingbin Yan (Shanghai Children's Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine)
  • Received : 2022.06.06
  • Accepted : 2022.10.03
  • Published : 2023.04.30
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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

Acknowledgement

This research was supported by the National Key Research and Development Program of China (2019YFA0801402) and the National Natural Science Foundation of China (81971421, 81471485), Shanghai key clinical specialty project (shslczdzk05705), Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20212200).

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