Sepsis-related myocardial injury is associated with Mst1 upregulation, mitochondrial dysfunction and the Drp1/F-actin signaling pathway

  • Xiuling Shang
  • Jun Li
  • Rongguo YuEmail author
  • Pengli ZhuEmail author
  • Yingrui Zhang
  • Jingqing Xu
  • Kaihua Chen
  • Min Li
Original Paper


LPS-induced septic cardiomyopathy has been found to be connected with mitochondrial stress through unknown mechanisms. Mitochondrial fission is an early event in mitochondrial dysfunction. The aim of our study was to determine the role and regulatory mechanism of mitochondrial fission in the progression of LPS-induced septic cardiomyopathy, with a particular focus on Mst1 and F-actin. Our data demonstrated that Mst1 expression was rapidly upregulated in LPS-treated hearts and that increased Mst1 promoted cardiomyocyte death by inducing mitochondrial stress. Mechanistically, elevated expression of Mst1 upregulated Drp1, and the latter initiated mitochondrial fission. Excessive mitochondrial fission caused mitochondrial oxidative injury, mitochondrial membrane potential reduction, mitochondrial proapoptotic element translocation into the cytoplasm/nucleus, mitochondrial energy dysfunction and mitochondrial apoptosis activation. Inhibition of mitochondrial fission sustained mitochondrial function and favored cardiomyocyte survival. Furthermore, we identified F-actin degradation as an apparent downstream event of mitochondrial fission activation in the context of LPS-induced septic cardiomyopathy. Stabilization of F-actin attenuated fission-mediated cardiomyocyte death. Altogether, our results define the Mst1/Drp1/mitochondrial fission/F-actin axis as a new signaling pathway that mediates LPS-related septic cardiomyopathy by inducing mitochondrial stress and cardiomyocyte death. Therefore, Mst1 expression, mitochondrial fission modification and F-actin stabilization may serve as potential therapeutic targets for sepsis-related myocardial injury.


LPS Septic cardiomyopathy Mst1 F-actin Mitochondrial fission 



The authors are grateful to the Institute of Basic Medicine Science of Qingdao Municipal Hospital.

Author contributions

XS and JL involved in conception and design, performance of experiments, data analysis and interpretation, and manuscript writing; RY and PZ involved in data analysis and interpretation; YZ, JX, KC and ML involved in conception and design, data analysis and interpretation, financial support, and final approval of manuscript.


This work was supported by Natural Science Foundation of Fujian (Grant number: (2015) 269) and high-level hospital grants from Fujian Provincial Hospital, Fujian province, China (Grant number: (2017) 510#). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors have declared that they have no conflicts of interest.


  1. Abdel-Hamid AAM, Firgany AEL (2018) Favorable outcomes of metformin on coronary microvasculature in experimental diabetic cardiomyopathy. J Mol Histol 49:639–649. CrossRefGoogle Scholar
  2. Abdulmahdi W et al (2017) HMGB1 redox during sepsis. Redox Biol 13:600–607. CrossRefGoogle Scholar
  3. Abeysuriya RG, Lockley SW, Robinson PA, Postnova S (2018) A unified model of melatonin, 6-sulfatoxymelatonin, and sleep dynamics. J Pineal Res. Google Scholar
  4. Angelova PR et al (2018) Mitochondrial dysfunction in Parkinsonian mesenchymal stem cells impairs differentiation. Redox Biol 14:474–484. CrossRefGoogle Scholar
  5. Antoniou C, Chatzimichail G, Xenofontos R, Pavlou JJ, Panagiotou E, Christou A, Fotopoulos V (2017) Melatonin systemically ameliorates drought stress-induced damage in Medicago sativa plants by modulating nitro-oxidative homeostasis and proline metabolism. J Pineal Res. Google Scholar
  6. Antunes F, Brito PM (2017) Quantitative biology of hydrogen peroxide signaling. Redox Biol 13:1–7. CrossRefGoogle Scholar
  7. Areti A, Komirishetty P, Akuthota M, Malik RA, Kumar A (2017) Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy. J Pineal Res. Google Scholar
  8. Armartmuntree N et al (2018) Prolonged oxidative stress down-regulates Early B cell factor 1 with inhibition of its tumor suppressive function against cholangiocarcinoma genesis. Redox Biol 14:637–644. CrossRefGoogle Scholar
  9. Ba X, Boldogh I (2018) 8-Oxoguanine DNA glycosylase 1: beyond repair of the oxidatively modified base lesions. Redox Biol 14:669–678. CrossRefGoogle Scholar
  10. Bi J et al (2018) Irisin alleviates liver ischemia-reperfusion injury by inhibiting excessive mitochondrial fission, promoting mitochondrial biogenesis and decreasing oxidative stress. Redox Biol 20:296–306. CrossRefGoogle Scholar
  11. Bikfalvi A (2017) History and conceptual developments in vascular biology and angiogenesis research: a personal view. Angiogenesis 20:463–478. CrossRefGoogle Scholar
  12. Blackburn NJR et al (2017) Methylglyoxal-derived advanced glycation end products contribute to negative cardiac remodeling and dysfunction post-myocardial infarction. Basic Res Cardiol. Google Scholar
  13. Blazquez-Castro A (2017) Direct 1O2 optical excitation: a tool for redox biology. Redox Biol 13:39–59. CrossRefGoogle Scholar
  14. Boga JA, Caballero B, Potes Y, Perez-Martinez Z, Reiter RJ, Vega-Naredo I, Coto-Montes A (2018) Therapeutic potential of melatonin related to its role as an autophagy regulator: a review. J Pineal Res. Google Scholar
  15. Brazao V et al (2017) Melatonin: antioxidant and modulatory properties in age-related changes during Trypanosoma cruzi infection. J Pineal Res. Google Scholar
  16. Cai H, Wang C (2017) Graphical review: the redox dark side of e-cigarettes; exposure to oxidants and public health concerns. Redox Biol 13:402–406. CrossRefGoogle Scholar
  17. Cai SY et al (2017) HsfA1a upregulates melatonin biosynthesis to confer cadmium tolerance in tomato plants. J Pineal Res. Google Scholar
  18. Caja S, Enriquez JA (2017) Mitochondria in endothelial cells: sensors and integrators of environmental cues. Redox Biol 12:821–827. CrossRefGoogle Scholar
  19. 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. Google Scholar
  20. Chandra M et al (2018) Cardiac-specific inactivation of LPP3 in mice leads to myocardial dysfunction and heart failure. Redox Biol 14:261–271. CrossRefGoogle Scholar
  21. Chen LY et al (2017) Melatonin successfully rescues hippocampal bioenergetics and improves cognitive function following drug intoxication by promoting Nrf2-ARE signaling activity. J Pineal Res. Google Scholar
  22. Chen T et al (2018) Sirt1-Sirt3 axis regulates human blood-brain barrier permeability in response to ischemia. Redox Biol 14:229–236. CrossRefGoogle Scholar
  23. Choi GH, Lee HY, Back K (2017a) Chloroplast overexpression of rice caffeic acid O-methyltransferase increases melatonin production in chloroplasts via the 5-methoxytryptamine pathway in transgenic rice plants. J Pineal Res. Google Scholar
  24. Choi SI, Lee E, Akuzum B, Jeong JB, Maeng YS, Kim TI, Kim EK (2017b) Melatonin reduces endoplasmic reticulum stress and corneal dystrophy-associated TGFBIp through activation of endoplasmic reticulum-associated protein degradation. J Pineal Res. Google Scholar
  25. Cobley JN, Close GL, Bailey DM, Davison GW (2017) Exercise redox biochemistry: conceptual, methodological and technical recommendations. Redox Biol 12:540–548. CrossRefGoogle Scholar
  26. Cortese-Krott MM et al (2018) Identification of a soluble guanylate cyclase in RBCs: preserved activity in patients with coronary artery disease. Redox Biol 14:328–337. CrossRefGoogle Scholar
  27. Ding M et al (2018) Dynamin-related protein 1-mediated mitochondrial fission contributes to post-traumatic cardiac dysfunction in rats and the protective effect of melatonin. J Pineal Res. Google Scholar
  28. Dominguez-Rodriguez A et al (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. Google Scholar
  29. Ji K et al (2018) Regulation of apoptosis and radiation sensitization in lung cancer cells via the Sirt1/NF-kappaB/Smac pathway. Cell Physiol Biochem 48:304–316. CrossRefGoogle Scholar
  30. Jin Q et al (2018) DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways. Redox Biol 14:576–587. CrossRefGoogle Scholar
  31. Karwi QG, Bice JS, Baxter GF (2017) Pre- and postconditioning the heart with hydrogen sulfide (H2S) against ischemia/reperfusion injury in vivo: a systematic review and meta-analysis. Basic Res Cardiol. Google Scholar
  32. Kiel AM, Goodwill AG, Noblet JN, Barnard AL, Sassoon DJ, Tune JD (2017) Regulation of myocardial oxygen delivery in response to graded reductions in hematocrit: role of K+ channels. Basic Res Cardiol. Google Scholar
  33. Kleinbongard P, Skyschally A, Gent S, Pesch M, Heusch G (2017) STAT3 as a common signal of ischemic conditioning: a lesson on “rigor and reproducibility” in preclinical studies on cardioprotection. Basic Res Cardiol. Google Scholar
  34. Landry NM, Cohen S, Dixon IMC (2017) Periostin in cardiovascular disease and development: a tale of two distinct roles. Basic Res Cardiol. Google Scholar
  35. Li W et al (2017) Long-term spironolactone treatment reduces coronary TRPC expression, vasoconstriction, and atherosclerosis in metabolic syndrome pigs. Basic Res Cardiol. Google Scholar
  36. Li H et al (2018a) Mst1 deletion attenuates renal ischaemia-reperfusion injury: the role of microtubule cytoskeleton dynamics, mitochondrial fission and the GSK3beta-p53 signalling pathway. Redox Biol 20:261–274. CrossRefGoogle Scholar
  37. Li R, Xin T, Li D, Wang C, Zhu H, Zhou H (2018b) Therapeutic effect of Sirtuin 3 on ameliorating nonalcoholic fatty liver disease: the role of the ERK-CREB pathway and Bnip3-mediated mitophagy. Redox Biol 18:229–243. CrossRefGoogle Scholar
  38. Li Z, Qiu R, Qiu X, Tian T (2018c) EYA4 promotes cell proliferation through downregulation of p27Kip1 in glioma. Cell Physiol Biochem 49:1856–1869. CrossRefGoogle Scholar
  39. Liu D, Zeng X, Li X, Mehta JL, Wang X (2017) Role of NLRP3 inflammasome in the pathogenesis of cardiovascular diseases. Basic Res Cardiol. Google Scholar
  40. Liu B, Xu L, Yu X, Jiao X, Yan J, Li W, Guo M (2018) Genistein inhibited estradiol-induced vascular endothelial cell injury by downregulating the FAK/focal adhesion pathway. Cell Physiol Biochem 49:2277–2292. CrossRefGoogle Scholar
  41. Maciel L, de Oliveira DF, da Costa GCV, Bisch PM, Nascimento JHM (2017) Cardioprotection by the transfer of coronary effluent from ischaemic preconditioned rat hearts: identification of cardioprotective humoral factors. Basic Res Cardiol. Google Scholar
  42. Maneechote C, Palee S, Chattipakorn SC, Chattipakorn N (2017) Roles of mitochondrial dynamics modulators in cardiac ischaemia/reperfusion injury. J Cell Mol Med 21:2643–2653. CrossRefGoogle Scholar
  43. Minton K (2015) Phagocytosis: mitochondria and phagosomes: better together. Nat Rev Immunol. Google Scholar
  44. Morell M, Burgos JI, Gonano LA, Vila Petroff M (2017) AMPK-dependent nitric oxide release provides contractile support during hyperosmotic stress. Basic Res Cardiol. Google Scholar
  45. Peterson YK et al (2017) Frizzled-5: a high affinity receptor for secreted frizzled-related protein-2 activation of nuclear factor of activated T-cells c3 signaling to promote angiogenesis. Angiogenesis 20:615–628. CrossRefGoogle Scholar
  46. Pryds K et al (2017) Effect of long-term remote ischemic conditioning in patients with chronic ischemic heart failure. Basic Res Cardiol. Google Scholar
  47. Reddy KRK et al (2018) Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is frequently upregulated in prostate cancer, and its overexpression conveys tumor growth and angiogenesis by metabolizing asymmetric dimethylarginine (ADMA). Angiogenesis 21:79–94. CrossRefGoogle Scholar
  48. Rossello X, Riquelme JA, He Z, Taferner S, Vanhaesebroeck B, Davidson SM, Yellon DM (2017) The role of PI3Kα isoform in cardioprotection. Basic Res Cardiol. Google Scholar
  49. Schluter KD, Wolf A, Weber M, Schreckenberg R, Schulz R (2017) Oxidized low-density lipoprotein (oxLDL) affects load-free cell shortening of cardiomyocytes in a proprotein convertase subtilisin/kexin 9 (PCSK9)-dependent way. Basic Res Cardiol. Google Scholar
  50. Schulz R, Agg B, Ferdinandy P (2017) Survival pathways in cardiac conditioning: individual data vs. meta-analyses. What do we learn? Basic Res Cardiol. Google Scholar
  51. Wang X, Song Q (2018) Mst1 regulates post-infarction cardiac injury through the JNK-Drp1-mitochondrial fission pathway. Cell Mol Biol Lett. Google Scholar
  52. Yan H, Qiu C, Sun W, Gu M, Xiao F, Zou J, Zhang L (2018) Yap regulates gastric cancer survival and migration via SIRT1/Mfn2/mitophagy. Oncol Rep 39:1671–1681. Google Scholar
  53. Yang Y et al (2016) The emerging role of Toll-like receptor 4 in myocardial inflammation. Cell Death Dis. Google Scholar
  54. Yu W, Xu M, Zhang T, Zhang Q, Zou C (2018) Mst1 promotes cardiac ischemia-reperfusion injury by inhibiting the ERK-CREB pathway and repressing FUNDC1-mediated mitophagy. J Physiol Sci. Google Scholar
  55. Zhang W, Liu K, Pei Y, Ma J, Tan J, Zhao J (2018) Mst1 regulates non-small cell lung cancer A549 cell apoptosis by inducing mitochondrial damage via ROCK1/Factin pathways. Int J Oncol. Google Scholar
  56. Zhao H, Pan W, Chen L, Luo Y, Xu R (2018a) Nur77 promotes cerebral ischemia-reperfusion injury via activating INF2-mediated mitochondrial fragmentation. J Mol Histol 49:599–613. CrossRefGoogle Scholar
  57. Zhao Q et al (2018b) Effect of Mst1 on endometriosis apoptosis and migration: role of Drp1-related mitochondrial fission and Parkin-required mitophagy. Cell Physiol Biochem 45:1172–1190. CrossRefGoogle Scholar
  58. Zhou H et al (2017) Mff-dependent mitochondrial fission contributes to the pathogenesis of cardiac microvasculature ischemia/reperfusion injury via induction of mROS-mediated cardiolipin oxidation and HK2/VDAC1 disassociation-involved mPTP opening. J Am Heart Assoc. Google Scholar
  59. Zhou H et al (2018a) Effects of melatonin on fatty liver disease: the role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy. J Pineal Res. Google Scholar
  60. Zhou H et al (2018b) NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α. Basic Res Cardiol. Google Scholar
  61. Zhou H, Shi C, Hu S, Zhu H, Ren J, Chen Y (2018c) BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways. Angiogenesis 21:599–615. CrossRefGoogle Scholar
  62. Zhou H, Wang J, Hu S, Zhu H, Toanc S, Ren J (2018d) BI1 alleviates cardiac microvascular ischemia-reperfusion injury via modifying mitochondrial fission and inhibiting XO/ROS/F-actin pathways. J Cell Physiol. Google Scholar
  63. Zhou H, Wang J, Zhu P, Hu S, Ren J (2018e) Ripk3 regulates cardiac microvascular reperfusion injury: the role of IP3R-dependent calcium overload, XO-mediated oxidative stress and F-action/filopodia-based cellular migration. Cell Signal 45:12–22. CrossRefGoogle Scholar
  64. Zhou H, Wang S, Hu S, Chen Y, Ren J (2018f) ER-mitochondria microdomains in cardiac ischemia-reperfusion injury: a fresh perspective. Front Physiol. Google Scholar
  65. Zhou H, Wang S, Zhu P, Hu S, Chen Y, Ren J (2018g) Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol 15:335–346. CrossRefGoogle Scholar
  66. Zhou H, Yue Y, Wang J, Ma Q, Chen Y (2018h) Melatonin therapy for diabetic cardiomyopathy: a mechanism involving Syk-mitochondrial complex I-SERCA pathway. Cell Signal 47:88–100. CrossRefGoogle Scholar
  67. Zhu H et al (2018a) Melatonin protected cardiac microvascular endothelial cells against oxidative stress injury via suppression of IP3R-[Ca2+]c/VDAC-[Ca2+]m axis by activation of MAPK/ERK signaling pathway. Cell Stress Chaperones 23:101–113. CrossRefGoogle Scholar
  68. Zhu P et al (2018b) Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury: a mechanism involving calcium overload/XO/ROS/mPTP pathway. Redox Biol 16:157–168. CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Xiuling Shang
    • 1
  • Jun Li
    • 1
  • Rongguo Yu
    • 1
    Email author
  • Pengli Zhu
    • 2
    Email author
  • Yingrui Zhang
    • 1
  • Jingqing Xu
    • 1
  • Kaihua Chen
    • 1
  • Min Li
    • 1
  1. 1.Department of Critical Care Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care MedicineFujian Medical UniversityFuzhouChina
  2. 2.Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Provincial Institute of Clinical Geriatrics, Fujian Key Laboratory of Geriatrics, Fujian Provincial Center for GeriatricsFujian Medical UniversityFuzhouChina

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