Mammalian STE20-like Kinase 1 Knockdown Attenuates TNFα-Mediated Neurodegenerative Disease by Repressing the JNK Pathway and Mitochondrial Stress
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Neuroinflammation has been acknowledged as a primary factor contributing to the pathogenesis of neurodegenerative disease. However, the molecular mechanism underlying inflammation stress-mediated neuronal dysfunction is not fully understood. The aim of our study was to explore the influence of mammalian STE20-like kinase 1 (Mst1) in neuroinflammation using TNFα and CATH.a cells in vitro. The results of our study demonstrated that the expression of Mst1 was dose-dependently increased after TNFα treatment. Interestingly, knockdown of Mst1 using siRNA transfection significantly repressed TNFα-induced neuronal death. We also found that TNFα treatment was associated with mitochondrial stress, including mitochondrial ROS overloading, mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential reduction, and mitochondrial pro-apoptotic factor release. Interestingly, loss of Mst1 attenuated TNFα-triggered mitochondrial stress and sustained mitochondrial function in CATH.a cells. We found that Mst1 modulated mitochondrial homeostasis and cell viability via the JNK pathway in a TNFα-induced inflammatory environment. Inhibition of the JNK pathway abolished TNFα-mediated CATH.a cell death and mitochondrial malfunction, similar to the results obtained via silencing of Mst1. Taken together, our results indicate that inflammation-mediated neuronal dysfunction is implicated in Mst1 upregulation, which promotes mitochondrial stress and neuronal death by activating the JNK pathway. Accordingly, our study identifies the Mst1–JNK-mitochondria axis as a novel signaling pathway involved in neuroinflammation.
KeywordsMst1 JNK pathway Neuroinflammation Mitochondrial stress Apoptosis
CZG, and JCW conceived the research; CZG and CSW performed the experiments; all authors participated in discussing and revising the manuscript.
Compliance with Ethical Standards
Conflict of interest
The authors have declared that they have no conflict of interest.
- 6.Blackburn NJR, Vulesevic B, McNeill B, Cimenci CE, Ahmadi A, Gonzalez-Gomez M, Ostojic A, Zhong Z, Brownlee M, Beisswenger PJ, Milne RW, Suuronen EJ (2017) Methylglyoxal-derived advanced glycation end products contribute to negative cardiac remodeling and dysfunction post-myocardial infarction. Basic Res Cardiol 112:57CrossRefGoogle Scholar
- 15.Fukumoto M, Kondo K, Uni K, Ishiguro T, Hayashi M, Ueda S, Mori I, Niimi K, Tashiro F, Miyazaki S, Miyazaki JI, Inagaki S, Furuyama T (2018) Tip-cell behavior is regulated by transcription factor FoxO1 under hypoxic conditions in developing mouse retinas. Angiogenesis 21:203–214CrossRefGoogle Scholar
- 30.Cortese-Krott MM, Mergia E, Kramer CM, Luckstadt W, Yang J, Wolff G, Panknin C, Bracht T, Sitek B, Pernow J, Stasch JP, Feelisch M, Koesling D, Kelm M (2018) Identification of a soluble guanylate cyclase in RBCs: preserved activity in patients with coronary artery disease. Redox Biol 14:328–337CrossRefGoogle Scholar
- 33.Koentges C, Pepin ME, Musse C, Pfeil K, Alvarez SVV, Hoppe N, Hoffmann MM, Odening KE, Sossalla S, Zirlik A, Hein L, Bode C, Wende AR, Bugger H (2017) Gene expression analysis to identify mechanisms underlying heart failure susceptibility in mice and humans. Basic Res Cardiol 113:8CrossRefGoogle Scholar
- 34.Dominguez-Rodriguez A, Abreu-Gonzalez P, de la Torre-Hernandez JM, Gonzalez-Gonzalez J, Garcia-Camarero T, Consuegra-Sanchez L, Garcia-Saiz MD, Aldea-Perona A, Virgos-Aller T, Azpeitia A, Reiter RJ (2017) Effect of intravenous and intracoronary melatonin as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: results of the melatonin adjunct in the acute myocardial infarction treated with angioplasty trial. J Pineal Res 62:e12374CrossRefGoogle Scholar
- 43.Li W, Chen X, Riley AM, Hiett SC, Temm CJ, Beli E, Long X, Chakraborty S, Alloosh M, White FA, Grant MB, Sturek M, Obukhov AG (2017) Long-term spironolactone treatment reduces coronary TRPC expression, vasoconstriction, and atherosclerosis in metabolic syndrome pigs. Basic Res Cardiol 112:54CrossRefGoogle Scholar
- 54.Jang H, Na Y, Hong K, Lee S, Moon S, Cho M, Park M, Lee OH, Chang EM, Lee DR, Ko JJ, Lee WS, Choi Y (2017) Synergistic effect of melatonin and ghrelin in preventing cisplatin-induced ovarian damage via regulation of FOXO3a phosphorylation and binding to the p27(Kip1) promoter in primordial follicles. J Pineal Res 63:e12432CrossRefGoogle Scholar