{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:01:49Z","timestamp":1791496909127,"version":"4.3.4"},"reference-count":51,"publisher":"National Academy of Sciences","issue":"26","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,6,28]]},"abstract":"<jats:p>\n                    Mitochondria, a highly metabolically active organelle, have been shown to play an essential role in regulating innate immune function. Mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    uptake via the mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    uniporter (MCU) is an essential process regulating mitochondrial metabolism by targeting key enzymes involved in the tricarboxylic acid cycle (TCA). Accumulative evidence suggests MCU-dependent mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling may bridge the metabolic reprogramming and regulation of immune cell function. However, the mechanism by which MCU regulates inflammation and its related disease remains elusive. Here we report a critical role of MCU in promoting phagocytosis-dependent activation of NLRP3 (nucleotide-binding domain, leucine-rich repeat containing family, pyrin domain-containing 3) inflammasome by inhibiting phagolysosomal membrane repair. Myeloid deletion of MCU (\n                    <jats:italic>\n                      Mcu\n                      <jats:sup>\u0394mye<\/jats:sup>\n                    <\/jats:italic>\n                    ) resulted in an attenuated phagolysosomal rupture, leading to decreased caspase-1 cleavage and interleukin (IL)-1\u03b2 release, in response to silica or alum challenge. In contrast, other inflammasome agonists such as adenosine triphosphate (ATP), nigericin, poly(dA:dT), and flagellin induced normal IL-1\u03b2 release in\n                    <jats:italic>\n                      Mcu\n                      <jats:sup>\u0394mye<\/jats:sup>\n                    <\/jats:italic>\n                    macrophages. Mechanistically, we demonstrated that decreased NLRP3 inflammasome activation in\n                    <jats:italic>\n                      Mcu\n                      <jats:sup>\u0394mye<\/jats:sup>\n                    <\/jats:italic>\n                    macrophages was caused by improved phagolysosomal membrane repair mediated by ESCRT (endosomal sorting complex required for transport)-III complex. Furthermore,\n                    <jats:italic>\n                      Mcu\n                      <jats:sup>\u0394mye<\/jats:sup>\n                    <\/jats:italic>\n                    mice showed a pronounced decrease in immune cell recruitment and IL-1\u03b2 production in alum-induced peritonitis, a typical IL-1\u2013dependent inflammation model. In sum, our results identify a function of MCU in promoting phagocytosis-dependent NLRP3 inflammatory response via an ESCRT-mediated phagolysosomal membrane repair mechanism.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2123247119","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T00:00:48Z","timestamp":1655942448000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":46,"title":["Mitochondrial calcium uniporter promotes phagocytosis-dependent activation of the NLRP3 inflammasome"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6719-4880","authenticated-orcid":false,"given":"Hong","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lupeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6363-2748","authenticated-orcid":false,"given":"Haitao","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210"},{"name":"The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210"},{"name":"Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-031210-101405"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2015.7"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.58"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190545"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1631"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06939"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.05.016"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11588"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2608"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2339"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1117765109"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1990.70.2.391"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10230"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10234"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3412"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060614-034216"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1210718109"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-00843-2"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7201"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aax9093"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0032OC"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar5078"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201899753"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07961"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.121"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1247136"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar7607"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.03.020"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06421"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402658"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2014.07.008"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6646"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.11.001"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.02.006"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.563114"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1636"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.10.005"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09973"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2003236117"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.115.3.599"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2975"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1980"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.21"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.01.009"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.08.001"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-018-0052-8"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.06.002"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.06.017"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1100126108"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(08)03602-1"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3192"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2123247119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T00:00:50Z","timestamp":1655942450000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.2123247119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,22]]},"references-count":51,"journal-issue":{"issue":"26","published-print":{"date-parts":[[2022,6,28]]}},"alternative-id":["10.1073\/pnas.2123247119"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2123247119","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,22]]},"assertion":[{"value":"2021-12-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2123247119"}}