FUNDC1 Mediated Mitophagy Relieves Sepsis Myocardial Mitochondrial Dysfunction By Inhibiting Excessive Mitochondrial Fission

Research background and purposeWith the development of various antibiotics,clinical diagnosis and treatment technology,the cure rate of severe infection has been greatly improved,but sepsis is still one of the important reasons threatening patients’ lives.Once sepsis is combined with cardiac dysfunction,the mortality of patients can significantly increase.Recent studies have found that FUNDC1,as a receptor molecule mediating mitophagy on the outer membrane of mitochondria,is an essential protein for mitophagy.Mitophagy plays an important role in the pathogenesis of myocardial injury in many sepsis cases.Meanwhile,mitochondria are dynamic organelles that continuously formed by fission and fusion,and thus regulate the function of cellular stress.Therefore,exploring the role of FUNDC1 dependent mitophagy and mitochondrial division in sepsis induced myocardial injury and the specific regulatory molecular mechanism is expected to provide a new theoretical basis and therapeutic target for sepsis cardiac protection.So This project aims to:(1)By clarifying the influence of FUNDC1 gene expression change on mitochondrial mass,explore the specific mechanism in H9c2 cardiomyocyte sepsis model.(2)By clarifying whether FUNDC1 has an anti-septic effect on myocardial injury in vitro and its specific mechanism,it is expected to propose a new strategy for the intervention of septic myocardial injury.Methods1.H9c2 rat cardiomyocytes were treated with lipopolysaccharide(LPS)to establish sepsis cardiomyocyte model and confirm the establishment of the model by detecting mitochondrial function.2.Detected the expression of related proteins to determine FUNDC1 mediated mitophagy level in sepsis.3.Lentivirus infection was used to construct stably knockdown/overexpressedFUNDC1 H9c2 cells and control cells;Mitochondrial function and cell activity were detected.4.Detected the expression of related proteins to determine the mitochondrial dynamics of sepsis;Mitochondrial function and cell activity were detected after treatment with Mdivi-1.5.Sepsis cell model was established and DRP1 expression was detected in stable knockdown/overexpression of FUNDC1 cells.6.Mdivi-1 was added to sepsis cell models after stable knockdown of FUNDC1,and mitochondrial function and cell activity were detected.RESULTS1.In H9c2 cardiomyocyte sepsis model established by LPS treatment,ATP production decreased significantly,reactive oxygen species increased,and mitochondrial membrane potential increased.2.FUNDC1 mediated mitophagy was inhibited in septic cardiomyocyte models.Overexpression of FUNDC1 improved mitochondrial function and cell activity,while the results of FUNDC1 knockdown was opposite.3.Excessive activation of mitochondrial division mediated by DRP1 in septic cardiomyocyte model,and inhibition of it can improve mitochondrial function and cell activity.4.Overexpression of FUNDC1 could inhibit mitochondrial over-division in cardiomyocytes in sepsis,but inhibition of mitochondrial over division cannot improve the negative effect of FUNDC1 knockdown in sepsis.Conclusion1.Myocardial mitochondrial dysfunction in sepsis is associated with FUNDC1 mediated mitophagy inhibition,and enhancement of FUNDC1 mediated mitophagy can improve mitochondrial function and cell activity.2.Myocardial mitochondrial dysfunction in sepsis is related to the excessive activation of mitochondrial division,and after inhibiting mitochondrial division,mitochondrial function and cell activity are improved.3.The FUNDC1 mediated relationship between mitophagy and mitochondrial fission in septic cardiomyocytes is dominated by mitophagy,and enhanced mitophagy can inhibit excessive mitochondrial division and improve prognosis.