Abstract
Clasmatodendrosis is one of the irreversible astroglial degeneration, which is involved in seizure duration and its progression in the epileptic hippocampus. Although sustained heat shock protein 25 (HSP25) induction leads to this autophagic astroglial death, dysregulation of mitochondrial dynamics (aberrant mitochondrial elongation) is also involved in the pathogenesis in clasmatodendrosis. However, the underlying molecular mechanisms of accumulation of elongated mitochondria in clasmatodendritic astrocytes are elusive. In the present study, we found that clasmatodendritic astrocytes showed up-regulations of HSP25 expression, AKT serine (S) 473 and dynamin-related protein 1 (DRP1) S637 phosphorylations in the hippocampus of chronic epilepsy rats. 2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me; bardoxolone methyl or RTA 402) abrogated abnormal mitochondrial elongation by reducing HSP25 upregulation, AKT S473- and DRP1 S637 phosphorylations. Furthermore, HSP25 siRNA and 3-chloroacetyl-indole (3CAI, an AKT inhibitor) abolished AKT-DRP1-mediated mitochondrial elongation and attenuated clasmatodendrosis in CA1 astrocytes. These findings indicate that HSP25-AKT-mediated DRP1 S637 hyper-phosphorylation may lead to aberrant mitochondrial elongation, which may result in autophagic astroglial degeneration. Therefore, our findings suggest that the dysregulation of HSP25-AKT-DRP1-mediated mitochondrial dynamics may play an important role in clasmatodendrosis, which would have implications for the development of novel therapies against various neurological diseases related to astroglial degeneration.