Peroxiredoxin 5 Inhibits Glutamate-Induced Neuronal Cell Death through the Regulation of Calcineurin-Dependent Mitochondrial Dynamics in HT22 Cells

ABSTRACT

Glutamate is an essential neurotransmitter in the central nervous system (CNS). However, high glutamate concentrations can lead to neurodegenerative diseases. A hallmark of glutamate toxicity is high levels of reactive oxygen species (ROS), which can trigger Ca²⁺ influx and dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Peroxiredoxin 5 (Prx5) is a well-known cysteine-dependent peroxidase enzyme. However, the precise effects of Prx5 on glutamate toxicity are still unclear. In this study, we investigated the role of Prx5 in glutamate-induced neuronal cell death. We found that glutamate treatment induces endogenous Prx5 expression and Ca²⁺/calcineurin-dependent dephosphorylation of Drp1, resulting in mitochondrial fission and neuronal cell death. Our results indicate that Prx5 inhibits glutamate-induced mitochondrial fission through the regulation of Ca²⁺/calcineurin-dependent dephosphorylation of Drp1, and it does so by scavenging cytosolic and mitochondrial ROS. Therefore, we suggest that Ca²⁺/calcineurin-dependent mitochondrial dynamics are deeply associated with glutamate-induced neurotoxicity. Consequently, Prx5 may be used as a potential agent for developing therapies against glutamate-induced neurotoxicity and neurodegenerative diseases where it plays a key role.

KEYWORDS:

• Ca²⁺
• calcineurin
• HT22
• mitochondria
• peroxiredoxin 5
• ROS
• glutamate

ACKNOWLEDGMENTS

M.H.K. and D.-S.L. performed the experiments and wrote the paper. H.J.L., S.-R.L., H.-S.L., J.-W.H., and Y.C.B. designed the study and experiments.

This research was supported by National Research Foundation of Korea (NRF) grants funded by the Korea government (NRF-2015R1A4A1042271, NRF-2017R1A2B4008176 and MSIT, and NRF-2017R1A5A2015391) and the KRIBB Research Initiative Program (KGM4621922).

We have no conflicts of interest to declare.