School of Life Science, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
Mol Cell Biol. 2019 Sep 27;39(20). doi: 10.1128/MCB.00148-19. Print 2019 Oct 15.
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 Ca 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 Ca/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 Ca/calcineurin-dependent dephosphorylation of Drp1, and it does so by scavenging cytosolic and mitochondrial ROS. Therefore, we suggest that Ca/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.
谷氨酸是中枢神经系统（CNS）中的一种必需神经递质。然而，高浓度的谷氨酸会导致神经退行性疾病。谷氨酸毒性的一个标志是高水平的活性氧（ROS），它可以触发钙流入和与动力蛋白相关蛋白 1（Drp1）介导的线粒体裂变。过氧化物酶 5（Prx5）是一种众所周知的含半胱氨酸的过氧化物酶。然而，Prx5 对谷氨酸毒性的确切影响尚不清楚。在这项研究中，我们研究了 Prx5 在谷氨酸诱导的神经元细胞死亡中的作用。我们发现，谷氨酸处理诱导内源性 Prx5 表达和 Ca/钙调神经磷酸酶依赖性 Drp1 去磷酸化，导致线粒体裂变和神经元细胞死亡。我们的结果表明，Prx5 通过调节 Ca/钙调神经磷酸酶依赖性 Drp1 去磷酸化来抑制谷氨酸诱导的线粒体裂变，它通过清除细胞质和线粒体中的 ROS 来实现这一点。因此，我们认为 Ca/钙调神经磷酸酶依赖性线粒体动力学与谷氨酸诱导的神经毒性密切相关。因此，Prx5 可能被用作开发针对谷氨酸诱导的神经毒性和神经退行性疾病的治疗方法的潜在药物，因为它在这些疾病中起着关键作用。
