Reciprocal c-Abl-GPx1 regulation controls CA1 neuronal viability to oxidative stress via ERK1/2-DRP1-mediated mitochondrial dynamics

Abstract

Abelson murine leukemia viral oncogene homolog 1 (c-Abl, also known as ABL1) is a potent selenium-independent regulator of expression and activity of glutathione peroxidase-1 (GPx1) and extracellular signal-regulated kinase 1/2 (ERK1/2). Since GPx1-ERK1/2 pathway modulates dynamin-related protein 1 (DRP1) serine (S) 616 phosphorylation, we investigated whether c-Abl participates in GPx1-ERK1/2 interaction and DRP1-mediated mitochondrial dynamics in CA1 neurons in response to oxidative stress induced by L-buthionine sulfoximine (BSO, an oxidative stress inducer) and status epilepticus (SE). In the present study, BSO enhanced c-Abl tyrosine (Y) 245 phosphorylation, ERK1/2 activity and GPx1 upregulation in the CA1 region under physiological condition. Imatinib (a c-Abl inhibitor) ameliorated BSO-induced c-Abl Y245, but elicited further ERK1/2 phosphorylation without affecting GPx1 expression. GPx1 knockdown enhanced BSO-induced c-Abl Y245 phosphorylation, but decreased ERK1/2 activity. BSO also facilitated mitochondrial fission in CA1 neurons by augmenting DRP1 expression and its S616 phosphorylation in the CA1 region, which were diminished by GPx1 knockdown and U0126 (an ERK1/2 inhibitor), but reinforced by imatinib. SE increased c-Abl Y245 phosphorylation and mitochondrial length in CA1 neurons, accompanied by reduced GPx1 expression and ERK1/2 phosphorylation. Imatinib and N-acetylcysteine (NAC, an antioxidant) attenuated these post-SE events and CA1 neuronal death. However, GPx1 knockdown deteriorated SE-induced CA1 neuronal degeneration accompanied by augmenting c-Abl Y245 phosphorylation and mitochondrial elongation in CA1 neurons. These findings indicate that the impaired reciprocal regulation between c-Abl and GPx1 may cause CA1 neuronal degeneration in response to oxidative stress by abrogating ERK1/2-DRP1-mediated mitochondrial fission.