Mammalian STE20-like Kinase 1 Knockdown Attenuates TNFα-Mediated Neurodegenerative Disease by Repressing the JNK Pathway and Mitochondrial Stress

  • Chizi GengEmail author
  • Jianchao Wei
  • Chengsi Wu
Original Paper


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.


Mst1 JNK pathway Neuroinflammation Mitochondrial stress Apoptosis 


Authors Contribution

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.


  1. 1.
    Sochocka M, Diniz BS, Leszek J (2017) Inflammatory response in the CNS: friend or foe? Mol Neurobiol 54:8071–8089CrossRefGoogle Scholar
  2. 2.
    Ardestani A, Paroni F, Azizi Z, Kaur S, Khobragade V, Yuan T, Frogne T, Tao W, Oberholzer J, Pattou F, Conte JK, Maedler K (2014) MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes. Nat Med 20:385–397CrossRefGoogle Scholar
  3. 3.
    Yao S, Yan W (2018) Overexpression of Mst1 reduces gastric cancer cell viability by repressing the AMPK-Sirt3 pathway and activating mitochondrial fission. Onco Targets Ther 11:8465–8479CrossRefGoogle Scholar
  4. 4.
    Qian J, Fang D, Lu H, Cao Y, Zhang J, Ding R, Li L, Huo J (2018) Tanshinone IIA promotes IL2-mediated SW480 colorectal cancer cell apoptosis by triggering INF2-related mitochondrial fission and activating the Mst1–Hippo pathway. Biomed Pharmacother 108:1658–1669CrossRefGoogle Scholar
  5. 5.
    Bikfalvi A (2017) History and conceptual developments in vascular biology and angiogenesis research: a personal view. Angiogenesis 20:463–478CrossRefGoogle Scholar
  6. 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
  7. 7.
    Abdulmahdi W, Patel D, Rabadi MM, Azar T, Jules E, Lipphardt M, Hashemiyoon R, Ratliff BB (2017) HMGB1 redox during sepsis. Redox Biol 13:600–607CrossRefGoogle Scholar
  8. 8.
    Brazao V, Santello FH, Colato RP, Mazotti TT, Tazinafo LF, Toldo MPA, do Vale GT, Tirapelli CR, do Prado JC Jr (2017) Melatonin: antioxidant and modulatory properties in age-related changes during Trypanosoma cruzi infection. J Pineal Res 63:e12409CrossRefGoogle Scholar
  9. 9.
    Buijs N, Oosterink JE, Jessup M, Schierbeek H, Stolz DB, Houdijk AP, Geller DA, van Leeuwen PA (2017) A new key player in VEGF-dependent angiogenesis in human hepatocellular carcinoma: dimethylarginine dimethylaminohydrolase 1. Angiogenesis 20:557–565CrossRefGoogle Scholar
  10. 10.
    Casadonte L, Verhoeff BJ, Piek JJ, VanBavel E, Spaan JAE, Siebes M (2017) Influence of increased heart rate and aortic pressure on resting indices of functional coronary stenosis severity. Basic Res Cardiol 112:61CrossRefGoogle Scholar
  11. 11.
    Antunes F, Brito PM (2017) Quantitative biology of hydrogen peroxide signaling. Redox Biol 13:1–7CrossRefGoogle Scholar
  12. 12.
    Conradi LC, Brajic A, Cantelmo AR, Bouche A, Kalucka J, Pircher A, Bruning U, Teuwen LA, Vinckier S, Ghesquiere B, Dewerchin M, Carmeliet P (2017) Tumor vessel disintegration by maximum tolerable PFKFB3 blockade. Angiogenesis 20:599–613CrossRefGoogle Scholar
  13. 13.
    Chang SH, Yeh YH, Lee JL, Hsu YJ, Kuo CT, Chen WJ (2017) Transforming growth factor-beta-mediated CD44/STAT3 signaling contributes to the development of atrial fibrosis and fibrillation. Basic Res Cardiol 112:58CrossRefGoogle Scholar
  14. 14.
    Zhang M, Lin J, Wang S, Cheng Z, Hu J, Wang T, Man W, Yin T, Guo W, Gao E, Reiter RJ, Wang H, Sun D (2017) Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling. J Pineal Res 63:e12418CrossRefGoogle Scholar
  15. 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
  16. 16.
    Li H, Feng J, Zhang Y, Feng J, Wang Q, Zhao S, Meng P, Li J (2019) Mst1 deletion attenuates renal ischaemia-reperfusion injury: the role of microtubule cytoskeleton dynamics, mitochondrial fission and the GSK3beta-p53 signalling pathway. Redox Biol 20:261–274CrossRefGoogle Scholar
  17. 17.
    Cohen MV, Downey JM (2017) The impact of irreproducibility and competing protection from P2Y12 antagonists on the discovery of cardioprotective interventions. Basic Res Cardiol 112:64CrossRefGoogle Scholar
  18. 18.
    Chen T, Dai SH, Li X, Luo P, Zhu J, Wang YH, Fei Z, Jiang XF (2018) Sirt1-Sirt3 axis regulates human blood-brain barrier permeability in response to ischemia. Redox Biol 14:229–236CrossRefGoogle Scholar
  19. 19.
    Brazao V, Colato RP, Santello FH, Vale GTD, Gonzaga NA, Tirapelli CR, Prado JCD Jr (2018) Effects of melatonin on thymic and oxidative stress dysfunctions during Trypanosoma cruzi infection. J Pineal Res 65:e12510CrossRefGoogle Scholar
  20. 20.
    Zhou H, Shi C, Hu S, Zhu H, Ren J, Chen Y (2018) BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways. Angiogenesis 21:599–615CrossRefGoogle Scholar
  21. 21.
    Gonzalez NR, Liou R, Kurth F, Jiang H, Saver J (2018) Antiangiogenesis and medical therapy failure in intracranial atherosclerosis. Angiogenesis 21:23–35CrossRefGoogle Scholar
  22. 22.
    Hong H, Tao T, Chen S, Liang C, Qiu Y, Zhou Y, Zhang R (2017) MicroRNA-143 promotes cardiac ischemia-mediated mitochondrial impairment by the inhibition of protein kinase Cepsilon. Basic Res Cardiol 112:60CrossRefGoogle Scholar
  23. 23.
    Cai SY, Zhang Y, Xu YP, Qi ZY, Li MQ, Ahammed GJ, Xia XJ, Shi K, Zhou YH, Reiter RJ, Yu JQ, Zhou J (2017) HsfA1a upregulates melatonin biosynthesis to confer cadmium tolerance in tomato plants. J Pineal Res 62:e12387CrossRefGoogle Scholar
  24. 24.
    Hassanshahi M, Hassanshahi A, Khabbazi S, Su YW, Xian CJ (2017) Bone marrow sinusoidal endothelium: damage and potential regeneration following cancer radiotherapy or chemotherapy. Angiogenesis 20:427–442CrossRefGoogle Scholar
  25. 25.
    Hooshdaran B, Kolpakov MA, Guo X, Miller SA, Wang T, Tilley DG, Rafiq K, Sabri A (2017) Dual inhibition of cathepsin G and chymase reduces myocyte death and improves cardiac remodeling after myocardial ischemia reperfusion injury. Basic Res Cardiol 112:62CrossRefGoogle Scholar
  26. 26.
    Das N, Mandala A, Naaz S, Giri S, Jain M, Bandyopadhyay D, Reiter RJ, Roy SS (2017) Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice. J Pineal Res 62:e12404CrossRefGoogle Scholar
  27. 27.
    Zhou H, Wang J, Zhu P, Zhu H, Toan S, Hu S, Ren J, Chen Y (2018) NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2alpha. Basic Res Cardiol 113:23CrossRefGoogle Scholar
  28. 28.
    Galley HF, McCormick B, Wilson KL, Lowes DA, Colvin L, Torsney C (2017) Melatonin limits paclitaxel-induced mitochondrial dysfunction in vitro and protects against paclitaxel-induced neuropathic pain in the rat. J Pineal Res 63:e12444CrossRefGoogle Scholar
  29. 29.
    Hatori Y, Inouye S, Akagi R, Seyama T (2018) Local redox environment beneath biological membranes probed by palmitoylated-roGFP. Redox Biol 14:679–685CrossRefGoogle Scholar
  30. 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
  31. 31.
    Carloni S, Riparini G, Buonocore G, Balduini W (2017) Rapid modulation of the silent information regulator 1 by melatonin after hypoxia-ischemia in the neonatal rat brain. J Pineal Res 63:e12434CrossRefGoogle Scholar
  32. 32.
    Kelly P, Denver P, Satchell SC, Ackermann M, Konerding MA, Mitchell CA (2017) Microvascular ultrastructural changes precede cognitive impairment in the murine APPswe/PS1dE9 model of Alzheimer’s disease. Angiogenesis 20:567–580CrossRefGoogle Scholar
  33. 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. 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
  35. 35.
    Yuan F, Xie Q, Wu J, Bai Y, Mao B, Dong Y, Bi W, Ji G, Tao W, Wang Y, Yuan Z (2011) MST1 promotes apoptosis through regulating Sirt1-dependent p53 deacetylation. J Biol Chem 286:6940–6945CrossRefGoogle Scholar
  36. 36.
    Jin Q, Li R, Hu N, Xin T, Zhu P, Hu S, Ma S, Zhu H, Ren J, Zhou H (2018) DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways. Redox Biol 14:576–587CrossRefGoogle Scholar
  37. 37.
    Liu Z, Liu Y, Xu Q, Peng H, Tang Y, Yang T, Yu Z, Cheng G, Zhang G, Shi R (2017) Critical role of vascular peroxidase 1 in regulating endothelial nitric oxide synthase. Redox Biol 12:226–232CrossRefGoogle Scholar
  38. 38.
    Camare C, Pucelle M, Negre-Salvayre A, Salvayre R (2017) Angiogenesis in the atherosclerotic plaque. Redox Biol 12:18–34CrossRefGoogle Scholar
  39. 39.
    Gao L, Zhao YC, Liang Y, Lin XH, Tan YJ, Wu DD, Li XZ, Ye BZ, Kong FQ, Sheng JZ, Huang HF (2016) The impaired myocardial ischemic tolerance in adult offspring of diabetic pregnancy is restored by maternal melatonin treatment. J Pineal Res 61:340–352CrossRefGoogle Scholar
  40. 40.
    Fan T, Pi H, Li M, Ren Z, He Z, Zhu F, Tian L, Tu M, Xie J, Liu M, Li Y, Tan M, Li G, Qing W, Reiter RJ, Yu Z, Wu H, Zhou Z (2018) Inhibiting MT2-TFE3-dependent autophagy enhances melatonin-induced apoptosis in tongue squamous cell carcinoma. J Pineal Res 64:e12457CrossRefGoogle Scholar
  41. 41.
    Zhou H, Zhu P, Wang J, Zhu H, Ren J, Chen Y (2018) Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2alpha-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy. Cell Death Differ 25:1080–1093CrossRefGoogle Scholar
  42. 42.
    Nawaz IM, Chiodelli P, Rezzola S, Paganini G, Corsini M, Lodola A, Di Ianni A, Mor M, Presta M (2018) N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) inhibits the angiogenic activity of heparin-binding growth factors. Angiogenesis 21:47–59CrossRefGoogle Scholar
  43. 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
  44. 44.
    Dickinson JD, Sweeter JM, Warren KJ, Ahmad IM, De Deken X, Zimmerman MC, Brody SL (2018) Autophagy regulates DUOX1 localization and superoxide production in airway epithelial cells during chronic IL-13 stimulation. Redox Biol 14:272–284CrossRefGoogle Scholar
  45. 45.
    Zhou H, Zhu P, Guo J, Hu N, Wang S, Li D, Hu S, Ren J, Cao F, Chen Y (2017) Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury. Redox Biol 13:498–507CrossRefGoogle Scholar
  46. 46.
    Ganini D, Leinisch F, Kumar A, Jiang J, Tokar EJ, Malone CC, Petrovich RM, Mason RP (2017) Fluorescent proteins such as eGFP lead to catalytic oxidative stress in cells. Redox Biol 12:462–468CrossRefGoogle Scholar
  47. 47.
    Rossello X, Riquelme JA, He Z, Taferner S, Vanhaesebroeck B, Davidson SM, Yellon DM (2017) The role of PI3Kalpha isoform in cardioprotection. Basic Res Cardiol 112:66CrossRefGoogle Scholar
  48. 48.
    Pryds K, Nielsen RR, Jorsal A, Hansen MS, Ringgaard S, Refsgaard J, Kim WY, Petersen AK, Botker HE, Schmidt MR (2017) Effect of long-term remote ischemic conditioning in patients with chronic ischemic heart failure. Basic Res Cardiol 112:67CrossRefGoogle Scholar
  49. 49.
    Turner CJ, Badu-Nkansah K, Hynes RO (2017) Endothelium-derived fibronectin regulates neonatal vascular morphogenesis in an autocrine fashion. Angiogenesis 20:519–531CrossRefGoogle Scholar
  50. 50.
    Lee HY, Back K (2017) Melatonin is required for H2O2− and NO-mediated defense signaling through MAPKKK3 and OXI1 in Arabidopsis thaliana. J Pineal Res 62:e12379CrossRefGoogle Scholar
  51. 51.
    Koka S, Xia M, Chen Y, Bhat OM, Yuan X, Boini KM, Li PL (2017) Endothelial NLRP3 inflammasome activation and arterial neointima formation associated with acid sphingomyelinase during hypercholesterolemia. Redox Biol 13:336–344CrossRefGoogle Scholar
  52. 52.
    Zhou J, Zhang H, Wang H, Lutz AM, El Kaffas A, Tian L, Hristov D, Willmann JK (2017) Early prediction of tumor response to bevacizumab treatment in murine colon cancer models using three-dimensional dynamic contrast-enhanced ultrasound imaging. Angiogenesis 20:547–555CrossRefGoogle Scholar
  53. 53.
    Schulz R, Agg B, Ferdinandy P (2017) Survival pathways in cardiac conditioning: individual data vs. meta-analyses. What do we learn? Basic Res Cardiol 113:4CrossRefGoogle Scholar
  54. 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
  55. 55.
    Morell M, Burgos JI, Gonano LA, Vila Petroff M (2017) AMPK-dependent nitric oxide release provides contractile support during hyperosmotic stress. Basic Res Cardiol 113:7CrossRefGoogle Scholar
  56. 56.
    Espinosa-Diez C, Miguel V, Vallejo S, Sanchez FJ, Sandoval E, Blanco E, Cannata P, Peiro C, Sanchez-Ferrer CF, Lamas S (2018) Role of glutathione biosynthesis in endothelial dysfunction and fibrosis. Redox Biol 14:88–99CrossRefGoogle Scholar
  57. 57.
    van Beijnum JR, Nowak-Sliwinska P, van Berkel M, Wong TJ, Griffioen AW (2017) A genomic screen for angiosuppressor genes in the tumor endothelium identifies a multifaceted angiostatic role for bromodomain containing 7 (BRD7). Angiogenesis 20:641–654CrossRefGoogle Scholar
  58. 58.
    Li Z, Li X, Chen C, Chan MTV, Wu WKK, Shen J (2017) Melatonin inhibits nucleus pulposus (NP) cell proliferation and extracellular matrix (ECM) remodeling via the melatonin membrane receptors mediated PI3K-Akt pathway. J Pineal Res 63:e12435CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Neurology DepartmentBeijing Luhe Hospital, Capital Medical UniversityBeijingChina

Personalised recommendations