MicroRNA-593-5p contributes to cell death following exposure to 1-methyl-4-phenylpyridinium by targeting PTEN-induced putative kinase 1.

Abstract

Neurodegenerative diseases are characterized by a decline in neuronal function and structure, leading to neuronal death. Understanding the molecular mechanisms of neuronal death is crucial for developing therapeutics. MiRs are small noncoding RNAs that regulate gene expression by degrading target mRNAs or inhibiting translation. MiR dysregulation has been linked to many neurodegenerative diseases, but the underlying mechanisms are not well understood. As mitochondrial dysfunction is one of the common molecular mechanisms leading to neuronal death in many neurodegenerative diseases, here we studied miRs that modulate neuronal death caused by 1-methyl-4-phenylpyridinium (MPP+), an inhibitor of complex I in mitochondria. We identified miR-593-5p, levels of which were increased in SH-SY5Y human neuronal cells, after exposure to MPP+. We found that intracellular Ca2+, but not of reactive oxygen species, mediated this miR-593-5p increase. Furthermore, we found the increase in miR-593-5p was due to enhanced stability, not increased transcription or miR processing. Importantly, we show the increase in miR-593-5p contributed to MPP+-induced cell death. Our data revealed that miR-593-5p inhibits a signaling pathway involving PTEN-induced putative kinase 1 (PINK1) and Parkin, two proteins responsible for the removal of damaged mitochondria from cells, by targeting the coding sequence of PINK1 mRNA. Our findings suggest that miR-593-5p contributes to neuronal death resulting from MPP+ toxicity, in part, by impeding the PINK1/Parkin-mediated pathway that facilitates the clearance of damaged mitochondria. Taken together, our observations highlight the potential significance of inhibiting miR-593-5p as a therapeutic approach for neurodegenerative diseases.

• Authors: Myungsik Yoo, Doo Chul Choi, Aleta Murphy, Atiq M Ahsan, Eunsung Junn
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 299 Issue 5 Pg. 104709 (05 2023) ISSN: 1083-351X [Electronic] United States
• PMID: 37060996 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• 1-Methyl-4-phenylpyridinium
• MicroRNAs
• MIRN593 microRNA, human
• Protein Kinases
• PTEN-induced putative kinase
• Ubiquitin-Protein Ligases

Topics

• Humans
• 1-Methyl-4-phenylpyridinium (toxicity)
• Apoptosis
• Cell Death
• Cell Line, Tumor
• MicroRNAs (genetics, metabolism)
• Neuroblastoma (metabolism)
• Protein Kinases (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics)