Mitochondrial c-Fos May Increase the Vulnerability of Neuro2a Cells to Cellular Stressors

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Web End = J Mol Neurosci (2016) 59:106112 DOI 10.1007/s12031-015-0710-7

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Web End = Mitochondrial c-Fos May Increase the Vulnerability of Neuro2a Cells to Cellular Stressors

Yuki Kambe1 & Atsuro Miyata1

Received: 6 March 2015 /Accepted: 28 December 2015 /Published online: 14 January 2016 # Springer Science+Business Media New York 2016

Abstract Although c-Fos expression in mitochondria is known to increase under excitatory injury via kainic acid or N-methyl-D-aspartate injection, the authentic function of c-Fos in mitochondria remains unknown. We found that c-Fos expression in the mitochondria of neuroblastoma Neuro2a cells was augmented by oxygen and glucose deprivation (OGD), which is a common in vitro model for brain ischemia. Then we demonstrated that Neuro2a cells stably expressing c-Fos exclusively in the mitochondria were more vulnerable to stressors such as OGD, rotenone (which is known to induce mitochondrial dysfunction) and hydrogen peroxide (a reactive oxygen species). Since mitochondrial dysfunction and the generation of reactive oxygen species are known to be caused by OGD, our findings indicate that mitochondrial c-Fos increases neuronal vulnerability to brain ischemia. This suggests that mitochondrial c-Fos play a potential role in inducing neuronal death on, and can therefore act as a potential drug target for brain ischemia.

Keywords c-Fos . Mitochondria . Neuronal death

Introduction

The mitochondria are organelles that produce cellular energy in the form of ATP; they are also known to mediate

programmed cell death (Kambe et al. 2008; Wang and Youle 2009). Brain ischemia-related neuronal death occurs because of abnormal blood flow, which results in excitotoxicity of the affected neurons due to the dysregulation of intracellular ions (Nitatori et al. 1995). This process is known to be mediated by mitochondrial malfunctions, such as mitochondrial calcium overload (Schinzel et al. 2005), cytochrome C release (Perez-Pinzon et al. 1999; Sugawara et al. 1999), and the production of reactive oxygen species (ROS) (Piantadosi and Zhang 1996). In addition, drugs such as cyclospolin A and NIM811 have been shown to decrease neuronal death in brain ischemia by interrupting mitochondrial malfunction through the inhibition of mitochondrial permeability transition (Domanska-Janik et al. 2004; Hokari et al. 2010). It is, therefore, clear that mitochondria play an important role...