p38 Inhibitor Protects Mitochondrial Dysfunction by Induction of DJ-1 Mitochondrial Translocation After Subarachnoid Hemorrhage

• Published in: Journal of molecular neuroscience Vol. 66; no. 2; pp. 163 - 171
• Main Authors: Huang, Liyong, Hou, Yaqing, Wang, Lei, Xu, Xiahui, Guan, Qingkai, Li, Xiangsheng, Chen, Ying, Zhou, Wenke
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2018; Springer Nature B.V
• Subjects: Activation; Animals; Autophagy; Biomedical and Life Sciences; Biomedicine; Cell Biology; Depolarization; Hemorrhage; Homeostasis; Imidazoles - pharmacology; Inhibitors; Kinases; MAP kinase; Membrane potential; Membrane Potential, Mitochondrial; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial DNA; Neurochemistry; Neurology; Neurosciences; Oxidative stress; Oxyhemoglobin; Oxyhemoglobins - metabolism; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; p62 Protein; PARK7 protein; PC12 Cells; Phagocytosis; Protein Deglycase DJ-1 - metabolism; Protein kinase; Protein Kinase Inhibitors - pharmacology; Proteins; Proteomics; Pyridines - pharmacology; Rats; Reactive oxygen species; Reactive Oxygen Species - metabolism; Subarachnoid hemorrhage; Subarachnoid Hemorrhage - metabolism; Translocation; DJ-1; Mitochondrial dysfunction; p38; Autophagy; ROS
• ISSN: 0895-8696; 1559-1166
• DOI: 10.1007/s12031-018-1131-1

p38 mitogen-activated protein kinase (MAPK) is a major player in mitochondrial dysfunction after subarachnoid hemorrhage (SAH). Moreover, DJ-1, which responds to oxidative stress and translocates to mitochondria, maintains mitochondrial homeostasis. Although a few studies have demonstrated that DJ-1 indirectly regulates p38 activation, the relationship between DJ-1 and p38 in mitochondrial dysfunction after SAH has not been delineated. Using an in vitro SAH model, alterations in p38, p-p38, DJ-1, and autophagic-related protein expression were detected. As expected, p38 inhibitor significantly blocked excessive expression of p38 and p-p38 after SAH, whereas total DJ-1 expression and mitochondrial DJ-1 were up-regulated. Further analysis showed that p38 inhibitor significantly blocked oxyhemoglobin (OxyHb) induced mitochondrial dysfunction, including mitochondrial membrane potential depolarization and reactive oxygen species (ROS) release. In addition, p38 inhibitor restored OxyHb-induced abnormal autophagic flux at the initiation and formation stage by regulating Atg5, beclin-1, the ratio of LC3-II/LC3-I, and p62 expression. This study suggested that overexpression of p38 induced the accumulation of mitochondrial dysfunction partly due to abnormal activation of autophagy, which largely relied on DJ-1 mitochondrial translocation.