The Research Study Of Mitochondrial Selective Autophagy Induced By Newcastle Disease Virus

Newcastle disease virus(NDV)is an important pathogen of infectious diseases in worldwide,which cause serious economic losses to the poultry industry for its high morbidity and mortality.NDV maintains oncolytic characteristic and induces cell death via intrinsic and/or extrinsic apoptosis signaling pathways.In eukaryote,mitochondria is a double membrane intracellular organelle,which plays multiple important roles in maintaining homeostasis.There are increasing evidences that mitochondria play vital roles in antiviral immune responses,apoptosis and inflammation.Using various strategies of anti-immune responses,NDV is able to highly replicate in chicken cell lines and tumor cell lines and trigger apoptosis.Considering that mitochondria as one of the most important intracellular organelles for homeostasis maintenance,however,the roles of mitochondria in NDV infection processes are less studies.Using different strategies such as electron microscope(EM),indirect fluorescence assay(IFA),Western blotting(WB)and co-immunoprecipitation(Co-IP),in this study,we have identified that NDV disturbed fusionfission homeostasis,triggered mitophagy via Parkin-PINK1 signaling,and eventually elucidated the biological significance for the degradation of fragmented mitochondria on host anti-immune responses.In this study,the main contents were discussed as followed:1.We observed that NDV infection disturbed the fusion-fission homeostasis.Using EM and IFA methods,we have identified that NDV infection triggered morphological changes of mitochondria,disturbed mitochondrial fusion-fission homeostasis,and induced spatial redistribution and nuclear aggregation,which enhanced the interplay among intracellular organelles with mitochondria.2.We elucidated the molecular mechanism of mitochondrial homeostasis disturbed by NDV infection.Using IFA,WB and qPCR,we have identified that NDV early infection enhanced mitochondrial fusion process,while NDV late infection enhanced mitochondrial fission process.Furthermore,the mitochondrial fusion was regulated by MFN1,MFN2 and OPA1 proteins,while mitochondrial fission was mainly regulated by the phosphorylation of DRP1,mitochondrial translocation of DRP1,and the cleavage of DRP1 protein.3.We elucidated the degradation mechanism of fragmented mitochondria.NDV infection disturbed mitochondrial homeostasis,damaged intracellular mitochondria,and triggered mitochondrial fragmentation.Using IFA and WB methods,we further identified that NDV degraded the fragmented mitochondria mainly dependent on the classical Parkin-PINK1 mitophagy signaling.Additionally,endosome-lysosome was also involved into the degradation of fragmented mitochondria.4.We elucidated the inhibitive effect for the degradation of fragmented mitochondria on host innate immunity.Using WB,IFA and Co-IP methods,we identified that NDV inhibited the MAVS-dependent host innate immunity via the degradation of fragmented mitochondria in order to promote viral replication.On the one hand,NDV infection damaged mitochondria,decreased the mitochondrial membrane potential(??m),induced mitophagy to degrade MAVS adaptor,which inhibited the mitochondrial-dependent immune response;On the other hand,NDV disturbed fusion-fission homeostasis,changed the redistribution of MAVS on mitochondria,and eventually inhibited the MAVS dependent immune response.Taken together,in this study,based on research point about the influence of NDV infection on mitochondrial function,we have elucidated that NDV infection disturbed mitochondrial homeostasis and damaged mitochondria in tumor cells.We further clarified that NDV degraded fragmented mitochondria via mitophagy and endosome-lysosome pathways.Meanwhile,NDV infection degraded mitochondrial adaptor MAVS to inhibit innate immunity.All these data above help us to understand the replication mechanism of NDV and anti-immune response of NDV infection in tumor cells,which provide an new insight for the re-construction of oncolytic virus.