Department of Pharmacology, School of Medicine, Eulji University, Daejeon 34824, Korea.
Cells. 2021 Sep 23;10(10):2522. 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.
丙戊酸（VPA）是一种抗癫痫药物，已被发现可在癌细胞系中诱导线粒体功能障碍和自噬。我们用不同浓度的 VPA（1、5 和 10 mM）处理 SH-SY5Y 细胞系。该处理降低了细胞活力、ATP 产生和线粒体膜电位，并增加了活性氧的产生。此外，VPA 处理后线粒体 DNA 拷贝数呈剂量依赖性增加。Western blot 显示，线粒体生物发生相关蛋白（PGC-1α、TFAM 和 COX4）的水平增加，尽管 VPA 处理后雌激素相关受体表达降低。此外，VPA 处理增加了总 FOXO3a 和乙酰化 FOXO3a 蛋白水平。虽然 SIRT1 表达降低，但 SIRT3 表达增加，调节了线粒体中 FOXO3a 的乙酰化。此外，VPA 处理通过增加 LC3-II 水平和降低 p62 表达和 mTOR 磷酸化诱导自噬。我们认为，VPA 处理通过改变 SH-SY5Y 细胞系中 FOXO3a 的表达和翻译后修饰来诱导线粒体生物发生和自噬。
