Irisin ameliorates septic cardiomyopathy via inhibiting DRP1-related mitochondrial fission and normalizing the JNK-LATS2 signaling pathway

  • Ying Tan
  • Haichun Ouyang
  • Xiaochan Xiao
  • Jiankai ZhongEmail author
  • Maolong DongEmail author
Original Paper


Irisin plays a protective effect in acute and chronic myocardial damage, but its role in septic cardiomyopathy is unclear. The aim of our study was to explore the in vivo and in vitro effects of irisin using an LPS-induced septic cardiomyopathy model. Our results demonstrated that irisin treatment attenuated LPS-mediated cardiomyocyte death and myocardial dysfunction. At the molecular level, LPS application was associated with mitochondrial oxidative injury, cardiomyocyte ATP depletion and caspase-related apoptosis activation. In contrast, the irisin treatment sustained mitochondrial function by inhibiting DRP1-related mitochondrial fission and the reactivation of mitochondrial fission impaired the protective action of irisin on inflammation-attacked mitochondria and cardiomyocytes. Additionally, we found that irisin modulated DRP1-related mitochondrial fission through the JNK-LATS2 signaling pathway. JNK activation and/or LATS2 overexpression abolished the beneficial effects of irisin on LPS-mediated mitochondrial stress and cardiomyocyte death. Altogether, our results illustrate that LPS-mediated activation of DRP1-related mitochondrial fission through the JNK-LATS2 pathway participates in the pathogenesis of septic cardiomyopathy. Irisin could be used in the future as an effective therapy for sepsis-induced myocardial depression because it corrects DRP1-related mitochondrial fission and normalizes the JNK-LATS2 signaling pathway.


Irisin DRP1-related mitochondrial fission JNK-LATS2 signaling pathway 



Thanks for the assistance from PLA general hospital with respect to functional studies in vitro.


This work is supported by the National Natural Science Foundation of China (NO. 81372055 and NO. 81571895), Natural Science Foundation of Guangdong Province of China (No: 2018A030313067), and Key Specialist Department Training Project of Foshan City, Guangdong Province of China (No: Fspy 3-2015034).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. Adaniya SM, J OU, Cypress MW, Kusakari Y, Jhun BS (2019) Post-translational modifications of mitochondrial fission and fusion proteins in cardiac physiology and pathophysiology. Am J Physiol Cell Physiol.
  2. Botker HE et al (2018) Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res Cardiol 113:39. CrossRefGoogle Scholar
  3. Charpentier J, Luyt CE, Fulla Y, Vinsonneau C, Cariou A, Grabar S, Dhainaut JF, Mira JP, Chiche JD (2004) Brain natriuretic peptide: a marker of myocardial dysfunction and prognosis during severe sepsis. Crit Care Med 32:660–665CrossRefGoogle Scholar
  4. 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 14:229–236. CrossRefGoogle Scholar
  5. Cheng CF, Ku HC, Lin H (2018) PGC-1alpha as a pivotal factor in lipid and metabolic regulation. Int J Mol Sci 19:11.
  6. Chrifi I, Louzao-Martinez L, Brandt MM, van Dijk CGM, Bürgisser PE, Zhu C, Kros JM, Verhaar MC, Duncker DJ, Cheng C (2019) CMTM4 regulates angiogenesis by promoting cell surface recycling of VE-cadherin to endothelial adherens junctions. Angiogenesis 22:75–93. CrossRefGoogle Scholar
  7. Coverstone ED, Bach RG, Chen LS, Bierut LJ, Li AY, Lenzini PA, O’Neill HC, Spertus JA, Sucharov CC, Stitzel JA, Schilling JD, Cresci S (2018) A novel genetic marker of decreased inflammation and improved survival after acute myocardial infarction. Basic Res Cardiol 113:38. CrossRefGoogle Scholar
  8. Darden J, Payne LB, Zhao H, Chappell JC (2019) Excess vascular endothelial growth factor-a disrupts pericyte recruitment during blood vessel formation. Angiogenesis 22:167–183. CrossRefGoogle Scholar
  9. Davidson SM, Arjun S, Basalay MV, Bell RM, Bromage DI, Bøtker HE, Carr RD, Cunningham J, Ghosh AK, Heusch G, Ibanez B, Kleinbongard P, Lecour S, Maddock H, Ovize M, Walker M, Wiart M, Yellon DM (2018) The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection-evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology. Basic Res Cardiol 113:43. CrossRefGoogle Scholar
  10. Deussen A (2018) Mechanisms underlying coronary autoregulation continue to await clarification. Basic Res Cardiol 113:34. CrossRefGoogle Scholar
  11. Dong M, Hu N, Hua Y, Xu X, Kandadi MR, Guo R, Jiang S, Nair S, Hu D, Ren J (2013) Chronic Akt activation attenuated lipopolysaccharide-induced cardiac dysfunction via Akt/GSK3β-dependent inhibition of apoptosis and ER stress. Biochim Biophys Acta 6:848–863. CrossRefGoogle Scholar
  12. Dong H, Weng C, Bai R, Sheng J, Gao X, Li L, Xu Z (2018) The regulatory network of miR-141 in the inhibition of angiogenesis. Angiogenesis.
  13. Edwards KS, Ashraf S, Lomax TM, Wiseman JM, Hall ME, Gava FN, Hall JE, Hosler JP, Harmancey R (2018) Uncoupling protein 3 deficiency impairs myocardial fatty acid oxidation and contractile recovery following ischemia/reperfusion. Basic Res Cardiol 113:47. CrossRefGoogle Scholar
  14. Farber G, Parks MM, Lustgarten Guahmich N, Zhang Y, Monette S, Blanchard SC, di Lorenzo A, Blobel CP (2018) ADAM10 controls the differentiation of the coronary arterial endothelium. Angiogenesis.
  15. Faughnan ME, Gossage JR, Chakinala MM, Oh SP, Kasthuri R, Hughes CCW, McWilliams JP, Parambil JG, Vozoris N, Donaldson J, Paul G, Berry P, Sprecher DL (2019) Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia. Angiogenesis 22:145–155. CrossRefGoogle Scholar
  16. Flynn A, Chokkalingam Mani B, Mather PJ (2010) Sepsis-induced cardiomyopathy: a review of pathophysiologic mechanisms. Heart Fail Rev 15:605–611. CrossRefGoogle Scholar
  17. Frandsen JR, Narayanasamy P (2018) Neuroprotection through flavonoid: enhancement of the glyoxalase pathway. Redox Biol 14:465–473. CrossRefGoogle Scholar
  18. 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 21:203–214. CrossRefGoogle Scholar
  19. Gonzalez NR, Liou R, Kurth F, Jiang H, Saver J (2018) Antiangiogenesis and medical therapy failure in intracranial atherosclerosis. Angiogenesis 21:23–35. CrossRefGoogle Scholar
  20. Huang CY, Lai CH, Kuo CH, Chiang SF, Pai PY, Lin JY, Chang CF, Viswanadha VP, Kuo WW, Huang CY (2018) Inhibition of ERK-Drp1 signaling and mitochondria fragmentation alleviates IGF-IIR-induced mitochondria dysfunction during heart failure. J Mol Cell Cardiol 122:58–68. CrossRefGoogle Scholar
  21. 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 14:576–587. CrossRefGoogle Scholar
  22. Kamura K, Shin J, Kiyonari H, Abe T, Shioi G, Fukuhara A, Sasaki H (2018) Obesity in Yap transgenic mice is associated with TAZ downregulation. Biochem Biophys Res Commun 505:951–957. CrossRefGoogle Scholar
  23. Kanwar MK, Yu J, Zhou J (2018) Phytomelatonin: recent advances and future prospects. J Pineal Res 65:e12526. CrossRefGoogle Scholar
  24. Kokkinaki D, Hoffman M, Kalliora C, Kyriazis ID, Maning J, Lucchese AM, Shanmughapriya S, Tomar D, Park JY, Wang H, Yang XF, Madesh M, Lymperopoulos A, Koch WJ, Christofidou-Solomidou M, Drosatos K (2019) Chemically synthesized Secoisolariciresinol diglucoside (LGM2605) improves mitochondrial function in cardiac myocytes and alleviates septic cardiomyopathy. J Mol Cell Cardiol 127:232–245. CrossRefGoogle Scholar
  25. Li J, Cai SX, He Q, Zhang H, Friedberg D, Wang F, Redington AN (2018) Intravenous miR-144 reduces left ventricular remodeling after myocardial infarction. Basic Res Cardiol 113:36. CrossRefGoogle Scholar
  26. Li H, He F, Zhao X, Zhang Y, Chu X, Hua C, Qu Y, Duan Y, Ming L (2017) YAP inhibits the apoptosis and migration of human rectal cancer cells via suppression of JNK-Drp1-mitochondrial fission-HtrA2/Omi pathways. Cell Physiol Biochem 44:2073–2089. CrossRefGoogle Scholar
  27. Li R, Wang X, Wu S, Wu Y, Chen H, Xin J, Li H, Lan J, Xue K, Li X, Zhuo C, He J, Tang CS, Jiang W (2019) Irisin ameliorates angiotensin II-induced cardiomyocyte apoptosis through autophagy. J Cell Physiol.
  28. Li RL, Wu SS, Wu Y, Wang XX, Chen HY, Xin JJ, Li H, Lan J, Xue KY, Li X, Zhuo CL, Cai YY, He JH, Zhang HY, Tang CS, Wang W, Jiang W (2018) Irisin alleviates pressure overload-induced cardiac hypertrophy by inducing protective autophagy via mTOR-independent activation of the AMPK-ULK1 pathway. J Mol Cell Cardiol 121:242–255. CrossRefGoogle Scholar
  29. Li R, Xin T, Li D, Wang C, Zhu H, Zhou H (2018) 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
  30. Liu Z, Gan L, Zhang T, Ren Q, Sun C (2018) Melatonin alleviates adipose inflammation through elevating α-ketoglutarate and diverting adipose-derived exosomes to macrophages in mice. J Pineal Res 64:1.
  31. Liu J, Yan W, Zhao X, Jia Q, Wang J, Zhang H, Liu C, He K, Sun Z (2019) Sirt3 attenuates post-infarction cardiac injury via inhibiting mitochondrial fission and normalization of AMPK-Drp1 pathways. Cell Signal 53:1–13. CrossRefGoogle Scholar
  32. Maria S, Samsonraj RM, Munmun F, Glas J, Silvestros M, Kotlarczyk MP, Rylands R, Dudakovic A, van Wijnen AJ, Enderby LT, Lassila H, Dodda B, Davis VL, Balk J, Burow M, Bunnell BA, Witt-Enderby PA (2018) Biological effects of melatonin on osteoblast/osteoclast cocultures, bone, and quality of life: implications of a role for MT2 melatonin receptors, MEK1/2, and MEK5 in melatonin-mediated osteoblastogenesis. J Pineal Res 64:3.
  33. Matkovich SJ, al Khiami B, Efimov IR, Evans S, Vader J, Jain A, Brownstein BH, Hotchkiss RS, Mann DL (2017) Widespread down-regulation of cardiac mitochondrial and sarcomeric genes in patients with sepsis. Crit Care Med 45:407–414. CrossRefGoogle Scholar
  34. Meyer IS, Leuschner F (2018) The role of Wnt signaling in the healing myocardium: a focus on cell specificity. Basic Res Cardiol 113:44. CrossRefGoogle Scholar
  35. Moulis MF, Millet AM, Daloyau M, Miquel MC, Ronsin B, Wissinger B, Arnauné-Pelloquin L, Belenguer P (2017) OPA1 haploinsufficiency induces a BNIP3-dependent decrease in mitophagy in neurons: relevance to dominant optic atrophy. J Neurochem 140:485–494. CrossRefGoogle Scholar
  36. Nakamura M, Zhai P, Del Re DP, Maejima Y, Sadoshima J (2016) Mst1-mediated phosphorylation of Bcl-xL is required for myocardial reperfusion injury. JCI Insight 1:5.
  37. Nishimura A, Shimauchi T, Tanaka T, Shimoda K, Toyama T, Kitajima N, Ishikawa T, Shindo N, Numaga-Tomita T, Yasuda S, Sato Y, Kuwahara K, Kumagai Y, Akaike T, Ide T, Ojida A, Mori Y, Nishida M (2018) Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence. Sci Signal 11:eaat5185. CrossRefGoogle Scholar
  38. Pan P, Wang X, Liu D (2018) The potential mechanism of mitochondrial dysfunction in septic cardiomyopathy. J Int Med Res 46:2157–2169. CrossRefGoogle Scholar
  39. Pan P, Zhang H, Su L, Wang X, Liu D (2018) Melatonin balance the autophagy and apoptosis by regulating UCP2 in the LPS-induced cardiomyopathy. Molecules 23:3.
  40. Rusnati M, Borsotti P, Moroni E, Foglieni C, Chiodelli P, Carminati L, Pinessi D, Annis DS, Paiardi G, Bugatti A, Gori A, Longhi R, Belotti D, Mosher DF, Colombo G, Taraboletti G (2019) The calcium-binding type III repeats domain of thrombospondin-2 binds to fibroblast growth factor 2 (FGF2). Angiogenesis 22:133–144. CrossRefGoogle Scholar
  41. Sheng J, Li H, Dai Q, Lu C, Xu M, Zhang J, Feng J (2019) DUSP1 recuses diabetic nephropathy via repressing JNK-Mff-mitochondrial fission pathways. J Cell Physiol 234:3043–3057. CrossRefGoogle Scholar
  42. Shi C, Cai Y, Li Y, Li Y, Hu N, Ma S, Hu S, Zhu P, Wang W, Zhou H (2018) Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/CaMKII pathways. Redox Biol 14:59–71. CrossRefGoogle Scholar
  43. Sinha B, Wu Q, Li W, Tu Y, Sirianni AC, Chen Y, Jiang J, Zhang X, Chen W, Zhou S, Reiter RJ, Manning SM, Patel NJ, Aziz-Sultan AM, Inder TE, Friedlander RM, Fu J, Wang X (2018) Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor. J Pineal Res 64:1.
  44. Skobowiat C, Brożyna AA, Janjetovic Z, Jeayeng S, Oak ASW, Kim TK, Panich U, Reiter RJ, Slominski AT (2018) Melatonin and its derivatives counteract the ultraviolet B radiation-induced damage in human and porcine skin ex vivo. J Pineal Res 65:e12501. CrossRefGoogle Scholar
  45. Souza LEB, Beckenkamp LR, Sobral LM, Fantacini DMC, Melo FUF, Borges JS, Leopoldino AM, Kashima S, Covas DT (2018) Pre-culture in endothelial growth medium enhances the angiogenic properties of adipose-derived stem/stromal cells. Angiogenesis 21:15–22. CrossRefGoogle Scholar
  46. Tong W, Ju L, Qiu M, Xie Q, Chen Y, Shen W, Sun W, Wang W, Tian J (2016) Liraglutide ameliorates non-alcoholic fatty liver disease by enhancing mitochondrial architecture and promoting autophagy through the SIRT1/SIRT3-FOXO3a pathway. Hepatol Res 46:933–943. CrossRefGoogle Scholar
  47. Wang Z, Chen K, Han Y, Zhu H, Zhou X, Tan T, Zeng J, Zhang J, Liu Y, Li Y, Yao Y, Yi J, He D, Zhou J, Ma J, Zeng C (2018) Irisin protects heart against ischemia-reperfusion injury through a SOD2-dependent mitochondria mechanism. J Cardiovasc Pharmacol 72:259–269. CrossRefGoogle Scholar
  48. Wang X, Song Q (2018) Mst1 regulates post-infarction cardiac injury through the JNK-Drp1-mitochondrial fission pathway. Cell Mol Biol Lett 23:21. CrossRefGoogle Scholar
  49. Wang H, Zhao YT, Zhang S, Dubielecka PM, du J, Yano N, Chin YE, Zhuang S, Qin G, Zhao TC (2017) Irisin plays a pivotal role to protect the heart against ischemia and reperfusion injury. J Cell Physiol 232:3775–3785. CrossRefGoogle Scholar
  50. Xie Y, Lv Y, Zhang Y, Liang Z, Han L, Xie Y (2019) LATS2 promotes apoptosis in non-small cell lung cancer A549 cells via triggering Mff-dependent mitochondrial fission and activating the JNK signaling pathway. Biomed Pharmacother 109:679–689. CrossRefGoogle Scholar
  51. Xie C, Zhang Y, Tran TDN, Wang H, Li S, George EV, Zhuang H, Zhang P, Kandel A, Lai Y, Tang D, Reeves WH, Cheng H, Ding Y, Yang LJ (2015) Irisin controls growth, intracellular Ca2+ signals, and mitochondrial thermogenesis in cardiomyoblasts. PLoS One 10:e0136816. CrossRefGoogle Scholar
  52. Yang S, Li H, Chen L (2019) MicroRNA-140 attenuates myocardial ischemia-reperfusion injury through suppressing mitochondria-mediated apoptosis by targeting YES1. J Cell Biochem 120:3813–3821. CrossRefGoogle Scholar
  53. Yang J, Zhang R, Jiang X, Lv J, Li Y, Ye H, Liu W, Wang G, Zhang C, Zheng N, Dong M, Wang Y, Chen P, Santosh K, Jiang Y, Liu J (2018) Toll-like receptor 4-induced ryanodine receptor 2 oxidation and sarcoplasmic reticulum ca(2+) leakage promote cardiac contractile dysfunction in sepsis. J Biol Chem 293:794–807. CrossRefGoogle Scholar
  54. Zhang J, Qiu J, Zhou Y, Wang Y, Li H, Zhang T, Jiang Y, Gou K, Cui S (2018) LIM homeobox transcription factor Isl1 is required for melatonin synthesis in the pig pineal gland. J Pineal Res 65:e12481. CrossRefGoogle Scholar
  55. Zhao L, Zhuang J, Wang Y, Zhou D, Zhao D, Zhu S, Pu J, Zhang H, Yin M, Zhao W, Wang Z, Hong J (2019) Propofol ameliorates H9c2 cells apoptosis induced by oxygen glucose deprivation and reperfusion injury via inhibiting high levels of mitochondrial fusion and fission. Front Pharmacol 10:61. CrossRefGoogle Scholar
  56. Zhou H, Hu S, Jin Q, Shi C, Zhang Y, Zhu P, Ma Q, Tian F, Chen Y (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 6:3.
  57. Zhou X, Li R, Liu X, Wang L, Hui P, Chan L, Saha PK, Hu Z (2016) ROCK1 reduces mitochondrial content and irisin production in muscle suppressing adipocyte browning and impairing insulin sensitivity. Sci Rep 6:29669. CrossRefGoogle Scholar
  58. Zhou H, Li D, Zhu P, Ma Q, Toan S, Wang J, Hu S, Chen Y, Zhang Y (2018) Inhibitory effect of melatonin on necroptosis via repressing the Ripk3-PGAM5-CypD-mPTP pathway attenuates cardiac microvascular ischemia-reperfusion injury. J Pineal Res 65:e12503. CrossRefGoogle Scholar
  59. Zhou H, Ma Q, Zhu P, Ren J, Reiter RJ, Chen Y (2018) Protective role of melatonin in cardiac ischemia-reperfusion injury: from pathogenesis to targeted therapy. J Pineal Res 64:3.
  60. Zhou J, Shi M, Li M, Cheng L, Yang J, Huang X (2019) Sirtuin 3 inhibition induces mitochondrial stress in tongue cancer by targeting mitochondrial fission and the JNK-Fis1 biological axis. Cell Stress Chaperones 24:369–383. CrossRefGoogle Scholar
  61. Zhou H, Wang S, Hu S, Chen Y, Ren J (2018) ER-mitochondria microdomains in cardiac ischemia-reperfusion injury: a fresh perspective. Front Physiol 9:755. CrossRefGoogle Scholar
  62. Zhou H, Wang J, Hu S, Zhu H, Toanc S, Ren J (2019) BI1 alleviates cardiac microvascular ischemia-reperfusion injury via modifying mitochondrial fission and inhibiting XO/ROS/F-actin pathways. J Cell Physiol 234:5056–5069. CrossRefGoogle Scholar
  63. Zhou H, Yue Y, Wang J, Ma Q, Chen Y (2018) Melatonin therapy for diabetic cardiomyopathy: a mechanism involving Syk-mitochondrial complex I-SERCA pathway. Cell Signal 47:88–100. CrossRefGoogle Scholar
  64. 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 13:498–507. CrossRefGoogle Scholar
  65. Zhu P, Hu S, Jin Q, Li D, Tian F, Toan S, Li Y, Zhou H, Chen Y (2018) 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

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© Cell Stress Society International 2019

Authors and Affiliations

  1. 1.Department of Emergency Medicine, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
  2. 2.Department of Cardiology, Shunde HospitalSouthern Medical UniversityFoshanChina
  3. 3.Department of Burns, Nanfang HospitalSouthern Medical UniversityGuangzhouChina

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