{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:32:20Z","timestamp":1792805540828,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,27]],"date-time":"2025-04-27T00:00:00Z","timestamp":1745712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32102619"],"award-info":[{"award-number":["32102619"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["KFKT2024016"],"award-info":[{"award-number":["KFKT2024016"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Open Project Program of Beijing Key Laboratory of Traditional Chinese Veterinary Medicine at Beijing University of Agriculture","award":["32102619"],"award-info":[{"award-number":["32102619"]}],"id":[{"id":"https:\/\/ror.org\/03t9adt98","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Open Project Program of Beijing Key Laboratory of Traditional Chinese Veterinary Medicine at Beijing University of Agriculture","award":["KFKT2024016"],"award-info":[{"award-number":["KFKT2024016"]}],"id":[{"id":"https:\/\/ror.org\/03t9adt98","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Influenza A virus (IAV) infection causes considerable morbidity and mortality worldwide, and the secondary bacterial infection further exacerbates the severity and fatality of the initial viral infection. Mitophagy plays an important role in host resistance to pathogen infection and immune response, while its role on pulmonary epithelial cells with viral and bacterial co-infection remains unclear. The present study reveals that the secondary Staphylococcus aureus infection significantly increased the viral and bacterial loads in human lung epithelial cells (A549) during the initial H1N1 infection. Meanwhile, the secondary S. aureus infection triggered more intense mitophagy in A549 cells by activating the PINK1\/Parkin signaling pathway. Notably, mitophagy could contribute to the proliferation of pathogens in A549 cells via the inhibition of cell apoptosis. Furthermore, based on an influenza A viral and secondary bacterial infected mouse model, we showed that activation of mitophagy was conducive to the proliferation of virus and bacteria in the lungs, aggravated the inflammatory damage and severe pneumonia at the same time, and eventually decreased the survival rate. The results elucidated the effect and the related molecular mechanism of mitophagy in pulmonary epithelial cells following IAV and secondary S. aureus infection for the first time, which will provide valuable information for the pathogenesis of virus\/bacteria interaction and new ideas for the treatment of severe pneumonia.<\/jats:p>","DOI":"10.3390\/ijms26094162","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T11:48:33Z","timestamp":1745840913000},"page":"4162","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Vital Role of PINK1\/Parkin-Mediated Mitophagy of Pulmonary Epithelial Cells in Severe Pneumonia Induced by IAV and Secondary Staphylococcus aureus Infection"],"prefix":"10.3390","volume":"26","author":[{"given":"Caiyun","family":"Huo","sequence":"first","affiliation":[{"name":"Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuli","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijing","family":"Su","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Dong","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Traditional Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7009-8451","authenticated-orcid":false,"given":"Yanxin","family":"Hu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3359-3925","authenticated-orcid":false,"given":"Hanchun","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lakdawala, S.S., Lamirande, E.W., Suguitan, A.L., Wang, W., Santos, C.P., Vogel, L., Matsuoka, Y., Lindsley, W.G., Jin, H., and Subbarao, K. (2011). Eurasian-origin gene segments contribute to the transmissibility, aerosol release, and morphology of the 2009 pandemic H1N1 influenza virus. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002443"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.chom.2007.09.001","article-title":"Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia","volume":"2","author":"McAuley","year":"2007","journal-title":"Cell Host Microbe"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1164\/201001-0037OC","article-title":"Pandemic 2009 influenza A in Argentina: A study of 337 patients on mechanical ventilation","volume":"182","author":"Estenssoro","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1007\/s00134-010-1853-1","article-title":"Critically ill infants and children with influenza A (H1N1) in pediatric intensive care units in Argentina","volume":"36","author":"Farias","year":"2010","journal-title":"Intensive Care Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/s41579-023-00852-y","article-title":"Staphylococcus aureus host interactions and adaptation","volume":"21","author":"Howden","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"112728","DOI":"10.1016\/j.celrep.2023.112728","article-title":"Mitochondria-derived cell-to-cell communication","volume":"42","author":"Thierry","year":"2023","journal-title":"Cell Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrm3028","article-title":"Mechanisms of mitophagy","volume":"12","author":"Youle","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e00993-18","DOI":"10.1128\/JVI.00993-18","article-title":"Human Immunodeficiency Virus Type 1 gp120 and Tat Induce Mitochondrial Fragmentation and Incomplete Mitophagy in Human Neurons","volume":"92","author":"Spector","year":"2018","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cheng, J., Wang, Y., Yin, L., Liang, W., Zhang, J., Ma, C., Zhang, Y., Liu, B., Wang, J., and Zhao, W. (2023). The nonstructural protein 1 of respiratory syncytial virus hijacks host mitophagy as a novel mitophagy receptor to evade the type I IFN response in HEp-2 cells. mBio, 14.","DOI":"10.1128\/mbio.01480-23"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lee, J., and Ou, J.J. (2024). HCV-induced autophagy and innate immunity. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1305157"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Xu, D., Hu, G., Luo, J., Cheng, J., Wu, D., Cheng, L., Huang, X., Fu, S., and Liu, J. (2023). Staphylococcus aureus induces mitophagy to promote its survival within bovine mammary epithelial cells. Vet. Microbiol., 280.","DOI":"10.1016\/j.vetmic.2023.109697"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Narendra, D.P., Jin, S.M., Tanaka, A., Suen, D.F., Gautier, C.A., Shen, J., Cookson, M.R., and Youle, R.J. (2010). PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000298"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/ncb2012","article-title":"PINK1\/Parkin-mediated mitophagy is dependent on VDAC1 and p62\/SQSTM1","volume":"12","author":"Geisler","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"E91","DOI":"10.1152\/ajpendo.00006.2020","article-title":"Melatonin ameliorates excessive PINK1\/Parkin-mediated mitophagy by enhancing SIRT1 expression in granulosa cells of PCOS","volume":"319","author":"Yi","year":"2020","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1080\/15548627.2023.2247310","article-title":"Autophagy preserves hematopoietic stem cells by restraining MTORC1-mediated cellular anabolism","volume":"20","author":"Borsa","year":"2023","journal-title":"Autophagy"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6413","DOI":"10.1073\/pnas.1321114111","article-title":"Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence","volume":"111","author":"Kim","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1080\/15548627.2020.1823123","article-title":"LDHB inhibition induces mitophagy and facilitates the progression of CSFV infection","volume":"17","author":"Fan","year":"2021","journal-title":"Autophagy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"105502","DOI":"10.1016\/j.antiviral.2022.105502","article-title":"PI3K\/AKT-mediated autophagy inhibition facilitates mast cell activation to enhance severe inflammatory lung injury in influenza A virus- and secondary Staphylococcus aureus-infected mice","volume":"209","author":"Tang","year":"2023","journal-title":"Antiviral Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nri2975","article-title":"Mitochondria in innate immune responses","volume":"11","author":"West","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1038\/s41467-023-36614-w","article-title":"GSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis","volume":"14","author":"Wei","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.cell.2006.02.015","article-title":"Pathogen recognition and innate immunity","volume":"124","author":"Akira","year":"2006","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1080\/15548627.2019.1580089","article-title":"Influenza M2 protein regulates MAVS-mediated signaling pathway through interacting with MAVS and increasing ROS production","volume":"15","author":"Wang","year":"2019","journal-title":"Autophagy"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5153","DOI":"10.4049\/jimmunol.1301237","article-title":"Influenza A exacerbates Staphylococcus aureus pneumonia by attenuating IL-1beta production in mice","volume":"191","author":"Robinson","year":"2013","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.4049\/jimmunol.1002194","article-title":"Influenza A inhibits Th17-mediated host defense against bacterial pneumonia in mice","volume":"186","author":"Kudva","year":"2011","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.4049\/jimmunol.0902772","article-title":"Influenza infection leads to increased susceptibility to subsequent bacterial superinfection by impairing NK cell responses in the lung","volume":"184","author":"Small","year":"2010","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/325536a0","article-title":"Role of Staphylococcus protease in the development of influenza pneumonia","volume":"325","author":"Tashiro","year":"1987","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"ra7","DOI":"10.1126\/scisignal.2001147","article-title":"Mitochondrial membrane potential is required for MAVS-mediated antiviral signaling","volume":"4","author":"Koshiba","year":"2011","journal-title":"Sci. Signal"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kondapalli, C., Kazlauskaite, A., Zhang, N., Woodroof, H.I., Campbell, D.G., Gourlay, R., Burchell, L., Walden, H., Macartney, T.J., and Deak, M. (2012). PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol., 2.","DOI":"10.1098\/rsob.120080"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1080\/15548627.2020.1725375","article-title":"Influenza A virus protein PB1-F2 impairs innate immunity by inducing mitophagy","volume":"17","author":"Wang","year":"2021","journal-title":"Autophagy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"279","DOI":"10.4161\/auto.7.3.14487","article-title":"Selective autophagy mediated by autophagic adapter proteins","volume":"7","author":"Johansen","year":"2011","journal-title":"Autophagy"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nature14893","article-title":"The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy","volume":"524","author":"Lazarou","year":"2015","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/s41392-021-00849-0","article-title":"SARS-CoV-2-triggered mast cell rapid degranulation induces alveolar epithelial inflammation and lung injury","volume":"6","author":"Wu","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1038\/s41419-022-05091-2","article-title":"FUNDC1-mediated mitophagy and HIF1alpha activation drives pulmonary hypertension during hypoxia","volume":"13","author":"Liu","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"27879","DOI":"10.1074\/jbc.M110.119537","article-title":"Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming","volume":"285","author":"Ding","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/s41590-019-0324-2","article-title":"Listeria hijacks host mitophagy through a novel mitophagy receptor to evade killing","volume":"20","author":"Zhang","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Kim, S.J., Syed, G.H., and Siddiqui, A. (2013). Hepatitis C virus induces the mitochondrial translocation of Parkin and subsequent mitophagy. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003285"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kim, S.J., Khan, M., Quan, J., Till, A., Subramani, S., and Siddiqui, A. (2013). Hepatitis B virus disrupts mitochondrial dynamics: Induces fission and mitophagy to attenuate apoptosis. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003722"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.cell.2010.01.040","article-title":"The inflammasomes","volume":"140","author":"Schroder","year":"2010","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Huo, C., Xiao, K., Zhang, S., Tang, Y., Wang, M., Qi, P., Xiao, J., Tian, H., and Hu, Y. (2018). H5N1 Influenza a Virus Replicates Productively in Pancreatic Cells and Induces Apoptosis and Pro-Inflammatory Cytokine Response. Front. Cell Infect. Microbiol., 8.","DOI":"10.3389\/fcimb.2018.00386"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"661","DOI":"10.2147\/IJN.S221667","article-title":"Pre-Treatment with Zirconia Nanoparticles Reduces Inflammation Induced by the Pathogenic H5N1 Influenza Virus","volume":"15","author":"Huo","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Meng, D., Huo, C., Wang, M., Xiao, J., Liu, B., Wei, T., Dong, H., Zhang, G., Hu, Y., and Sun, L. (2016). Influenza A Viruses Replicate Productively in Mouse Mastocytoma Cells (P815) and Trigger Pro-inflammatory Cytokine and Chemokine Production through TLR3 Signaling Pathway. Front. Microbiol., 7.","DOI":"10.3389\/fmicb.2016.02130"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Gopal, R., Lee, B., McHugh, K.J., Rich, H.E., Ramanan, K., Mandalapu, S., Clay, M.E., Seger, P.J., Enelow, R.I., and Manni, M.L. (2018). STAT2 Signaling Regulates Macrophage Phenotype During Influenza and Bacterial Super-Infection. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02151"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Huo, C., Tang, Y., Li, X., Han, D., Gu, Q., Su, R., Liu, Y., Reiter, R.J., Liu, G., and Hu, Y. (2023). Melatonin alleviates lung injury in H1N1-infected mice by mast cell inactivation and cytokine storm suppression. PLoS Pathog., 19.","DOI":"10.1371\/journal.ppat.1011406"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4162\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:23:01Z","timestamp":1760030581000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,27]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26094162"],"URL":"https:\/\/doi.org\/10.3390\/ijms26094162","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,27]]}}}