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.

Comparison of the protective effect of cytosolic and mitochondrial Peroxiredoxin 5 against glutamate-induced neuronal cell death

“…As shown in Figure 1(B), glutamate increased HyPer-Cyto and HyPer-Mito fluorescence to similar levels for up to 9 h after treatment. However, HyPer-Mito showed a dramatic increase compared to HyPer-Cyto at 12 h. In a previous study, we confirmed that glutamate treatment increased the expression level of Prx5 in a time-/ concentration-dependent manner and that glutamate-induced ROS generation was related to the upregulation of Prx5 expression [13]. The present study showed that co-treatment with N-acetyl-L-cysteine (an intensive ROS scavenger) or MitoTEMPO (a mitochondrial ROS scavenger) downregulated Prx5 expression, indicating that the upregulation of Prx5 was related to glutamate-induced ROS generation (Figure 1(C)).…”

“…Of the six Prx subtypes, the antioxidant effect of Prx5 in various cellular systems has been well established. In previous studies, we reported that Prx5 reduces LPS-induced microglia activation and protects neuronal cells from neurotoxic substances, such as β-amyloid, iron, diethylhexyl phthalate, and glutamate [ 13 , 18 , 30–34 ]. These findings highlight the necessity of further study on the relationship between the antioxidant effects and intracellular location of Prx5.…”

“…We focused particularly on the correlation between glutamate-induced apoptosis and cytosolic/mitochondrial ROS. Our findings suggested a need for research on the casual relationship between cytosolic and mitochondrial ROS in glutamate-induced apoptosis [ 13 ]. It is not yet known whether cytosolic or mitochondrial ROS is of greater importance in glutamate toxicity.…”

Neuroprotective Effect of Tricyclic Pyridine Alkaloids from Fusarium lateritium SSF2, against Glutamate-Induced Oxidative Stress and Apoptosis in the HT22 Hippocampal Neuronal Cell Line

“…It is well known that glutamate-induced HT22 cell death is by the excessive levels of Ca 2+ [ 27 ]. Thus, we evaluated the effect of 4,6′-anhydrooxysporidinone on levels of Ca 2+ in glutamate-treated HT22 cells using a Fluo-4 AM dye, a membrane permeable fluorescent indicator for Ca 2+ .…”

Calcineurin Activation by Prion Protein Induces Neurotoxicity via Mitochondrial Reactive Oxygen Species

“…Our previous studies suggested that PrP 106-126 increases intracellular calcium levels and calcineurin (CaN) activity in neurons [39,40]. Other researchers have shown that increased calcium levels are associated with the mitochondrial apoptotic pathway in neurodegenerative diseases that involve prions [31,41]. When mitochondrial depolarization occurs with a sustained cytosolic rise in Ca 2+ , the cytosolic phosphatase activity of the serine/threonine phosphatase CaN is activated [42].…”