Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Etoposide Induces Mitochondrial Dysfunction and Cellular Senescence in Primary Cultured Rat Astrocytes

  • Bang, Minji (Department of Neuroscience, School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Kim, Do Gyeong (Department of Neuroscience, School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Gonzales, Edson Luck (Department of Neuroscience, School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Kwon, Kyoung Ja (Department of Neuroscience, School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Shin, Chan Young (Department of Neuroscience, School of Medicine and Center for Neuroscience Research, Konkuk University)
  • Received : 2019.09.16
  • Accepted : 2019.09.25
  • Published : 2019.11.01
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Abstract

Brain aging is an inevitable process characterized by structural and functional changes and is a major risk factor for neurodegenerative diseases. Most brain aging studies are focused on neurons and less on astrocytes which are the most abundant cells in the brain known to be in charge of various functions including the maintenance of brain physical formation, ion homeostasis, and secretion of various extracellular matrix proteins. Altered mitochondrial dynamics, defective mitophagy or mitochondrial damages are causative factors of mitochondrial dysfunction, which is linked to age-related disorders. Etoposide is an anti-cancer reagent which can induce DNA stress and cellular senescence of cancer cell lines. In this study, we investigated whether etoposide induces senescence and functional alterations in cultured rat astrocytes. Senescence-associated ${\beta}$-galactosidase (SA-${\beta}$-gal) activity was used as a cellular senescence marker. The results indicated that etoposide-treated astrocytes showed cellular senescence phenotypes including increased SA-${\beta}$-gal-positive cells number, increased nuclear size and increased senescence-associated secretory phenotypes (SASP) such as IL-6. We also observed a decreased expression of cell cycle markers, including PhosphoHistone H3/Histone H3 and CDK2, and dysregulation of cellular functions based on wound-healing, neuronal protection, and phagocytosis assays. Finally, mitochondrial dysfunction was noted through the determination of mitochondrial membrane potential using tetramethylrhodamine methyl ester (TMRM) and the measurement of mitochondrial oxygen consumption rate (OCR). These data suggest that etoposide can induce cellular senescence and mitochondrial dysfunction in astrocytes which may have implications in brain aging and neurodegenerative conditions.

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References

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