Acute Valproate Exposure Induces Mitochondrial Biogenesis and Autophagy with FOXO3a Modulation in SH-SY5Y Cells

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 10; p. 2522
• Main Authors: Jang, Eun-Hye, Lee, Jung-Ho, Kim, Soon-Ae
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23.09.2021; MDPI
• Subjects: Acetylation; Antibodies; Anticonvulsants - pharmacology; Antiepileptic agents; Autophagy; Autophagy - drug effects; Biosynthesis; Cancer; Cell culture; Cell Survival - drug effects; Cell viability; Copy number; Cytotoxicity; DNA, Mitochondrial - drug effects; DNA, Mitochondrial - metabolism; Epigenetics; Forkhead Box Protein O3 - drug effects; FOXO3 protein; FOXO3a; Humans; Mammals; Medical prognosis; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Membranes; mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial DNA; Neuroblastoma; Organelle Biogenesis; Oxidative stress; Phagocytosis; Phosphorylation; Proteins; Reactive oxygen species; Reagents; SIRT1 protein; Stress analysis; TOR protein; Tumor cell lines; Valproic acid; Valproic Acid - pharmacology; Western blotting; St Louis Missouri; United Kingdom > UK; United States > US; Switzerland; Japan; autophagy; FOXO3a; valproic acid; mitochondria
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10102522

Valproic acid (VPA) is an antiepileptic drug found to induce mitochondrial dysfunction and autophagy in cancer cell lines. We treated the SH-SY5Y cell line with various concentrations of VPA (1, 5, and 10 mM). The treatment decreased cell viability, ATP production, and mitochondrial membrane potential and increased reactive oxygen species production. In addition, the mitochondrial DNA copy number increased after VPA treatment in a dose-dependent manner. Western blotting showed that the levels of mitochondrial biogenesis-related proteins (PGC-1α, TFAM, and COX4) increased, though estrogen-related receptor expression decreased after VPA treatment. Further, VPA treatment increased the total and acetylated FOXO3a protein levels. Although SIRT1 expression was decreased, SIRT3 expression was increased, which regulated FOXO3 acetylation in the mitochondria. Furthermore, VPA treatment induced autophagy via increased LC3-II levels and decreased p62 expression and mTOR phosphorylation. We suggest that VPA treatment induces mitochondrial biogenesis and autophagy via changes in FOXO3a expression and posttranslational modification in the SH-SY5Y cell line.