{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T23:23:15Z","timestamp":1790032995766,"version":"4.0.1"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T00:00:00Z","timestamp":1607644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>NOD-like receptors (NLR) are intracellular sensors of the innate immune system, with the NLRP3 being a pro-inflammatory member that modulates cardiac ischemia-reperfusion injury (IRI) and metabolism. No information is available on a possible role of anti-inflammatory NLRs on IRI and metabolism in the intact heart. Here we hypothesize that the constitutively expressed, anti-inflammatory mitochondrial NLRX1, affects IRI and metabolism of the isolated mouse heart.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Isolated C57Bl\/6J and NLRX1 knock-out (KO) mouse hearts were perfused with a physiological mixture of the essential substrates (lactate, glucose, pyruvate, fatty acid, glutamine) and insulin. For the IRI studies, hearts were subjected to either mild (20\u00a0min) or severe (35\u00a0min) ischemia and IRI was determined at 60\u00a0min reperfusion. Inflammatory mediators (IL-6, TNF\u03b1) and survival pathways (mito-HKII, p-Akt, p-AMPK, p-STAT3) were analyzed at 5\u00a0min of reperfusion. For the metabolism studies, hearts were perfused for 35\u00a0min with either 5.5 mM\n                      <jats:sup>13<\/jats:sup>\n                      C-glucose or 0.4 mM\n                      <jats:sup>13<\/jats:sup>\n                      C-palmitate under normoxic conditions, followed by LC-MS analysis and integrated, stepwise, mass-isotopomeric flux analysis (MIMOSA).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NLRX1 KO significantly increased IRI (infarct size from 63% to 73%, end-diastolic pressure from 59 mmHg to 75 mmHg, and rate-pressure-product recovery from 15% to 6%), following severe, but not mild, ischemia. The increased IRI in NLRX1 KO hearts was associated with depressed Akt signaling at early reperfusion; other survival pathways or inflammatory parameters were not affected. Metabolically, NLRX1 KO hearts displayed increased lactate production and glucose oxidation relative to fatty acid oxidation, associated with increased pyruvate dehydrogenase flux and 10% higher cardiac oxygen consumption.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Deletion of the mitochondrially-located NOD-like sensor NLRX1 exacerbates severe cardiac IR injury, possibly through impaired Akt signaling, and increases cardiac glucose metabolism.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2020.591815","type":"journal-article","created":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T00:33:34Z","timestamp":1607646814000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["NLRX1 Deletion Increases Ischemia-Reperfusion Damage and Activates Glucose Metabolism in Mouse Heart"],"prefix":"10.3389","volume":"11","author":[{"given":"Hong","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rianne","family":"Nederlof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Bakker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengbo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen E.","family":"Girardin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus W.","family":"Hollmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina C.","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander M.","family":"Houten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"van Weeghel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard G.","family":"Kibbey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coert J.","family":"Zuurbier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvy304","article-title":"Innate immunity as a target for acute cardioprotection","volume":"115","author":"Zuurbier","year":"2019","journal-title":"Cardiovasc Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2017.161","article-title":"The NLRP3 inflammasome in acute myocardial infarction","volume":"15","author":"Toldo","year":"2018","journal-title":"Nat Rev Cardiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nature06501","article-title":"NLRX1 is a regulator of mitochondrial antiviral immunity","volume":"451","author":"Moore","year":"2008","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-018-3444-3","article-title":"The mitochondrial Nod-like receptor NLRX1 modifies apoptosis through SARM1","volume":"453","author":"Killackey","year":"2019","journal-title":"Mol Cell Biochem"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.03.026","article-title":"NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-\u03baB signaling pathways","volume":"34","author":"Allen","year":"2011","journal-title":"Immunity"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e3000451","DOI":"10.1371\/journal.pbio.3000451","article-title":"NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity","volume":"17","author":"Gharagozloo","year":"2019","journal-title":"PloS Biol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2019.02.018","article-title":"NLRX1 regulates TNF-\u03b1-induced mitochondria-lysosomal crosstalk to maintain the invasive and metastatic potential of breast cancer cells","volume":"1865","author":"Singh","year":"2019","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20161031","article-title":"NLRX1 dampens oxidative stress and apoptosis in tissue injury via control of mitochondrial activity","volume":"214","author":"Stokman","year":"2017","journal-title":"J Exp Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2016.06.013","article-title":"NLRX1 attenuates apoptosis and inflammatory responses in myocardial ischemia by inhibiting MAVS-dependent NLRP3 inflammasome activation","volume":"76","author":"Li","year":"2016","journal-title":"Mol Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12363","article-title":"Targeting hexokinase II to mitochondria to modulate energy metabolism and reduce ischaemia-reperfusion injury in heart","volume":"171","author":"Nederlof","year":"2014","journal-title":"Br J Pharmacol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s13105-017-0555-3","article-title":"Reducing mitochondrial bound hexokinase II mediates transition from non-injurious into injurious ischemia\/reperfusion of the intact heart","volume":"73","author":"Nederlof","year":"2016","journal-title":"J Physiol Biochem"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.111.244962","article-title":"Disruption of hexokinase II-mitochondrial binding blocks ischemic preconditioning and causes rapid cardiac necrosis","volume":"108","author":"Smeele","year":"2011","journal-title":"Circ Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2003.10.022","article-title":"Ischemic preconditioning activates AMPK in a PKC-dependent manner and induces GLUT4 up-regulation in the late phase of cardioprotection","volume":"61","author":"Nishino","year":"2004","journal-title":"Cardiovasc Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00374.2004","article-title":"Ischemic preconditioning protects by activating prosurvival kinases at reperfusion","volume":"288","author":"Hausenloy","year":"2005","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2004.06.019","article-title":"Genetic depletion of cardiac myocyte STAT-3 abolishes classical preconditioning","volume":"63","author":"Smith","year":"2004","journal-title":"Cardiovasc Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-011-0225-5","article-title":"The role of mitochondrial permeability transition in reperfusion-induced cardiomyocyte death depends on the duration of ischemia","volume":"106","author":"Ruiz-Meana","year":"2011","journal-title":"Basic Res Cardiol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-014-0325-8","article-title":"Cardioprotective efficacy depends critically on pharmacological dose, duration of ischaemia, health status of animals and choice of anaesthetic regimen: a case study with folic acid","volume":"12","author":"Zuurbier","year":"2014","journal-title":"J Transl Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-008-0743-y","article-title":"Limitation of myocardial infarct size in the clinical setting: current status and challenges in translating animal experiments into clinical therapy","volume":"103","author":"Miura","year":"2008","journal-title":"Basic Res Cardiol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2018.03.003","article-title":"Deletion of NLRX1 increases fatty acid metabolism and prevents diet-induced hepatic steatosis and metabolic syndrome","volume":"1864","author":"Kors","year":"2018","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.02.026","article-title":"Cardioprotection by metabolic shut-down and gradual wake-up","volume":"46","author":"Burwell","year":"2009","journal-title":"J Mol Cell Cardiol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/s0008-6363(96)00245-3","article-title":"Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological interventions","volume":"33","author":"Stanley","year":"1997","journal-title":"Cardiovasc Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15180","article-title":"Cardiac metabolism as a driver and therapeutic target of myocardial infarction","volume":"24","author":"Zuurbier","year":"2020","journal-title":"J Cell Mol Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1177\/1753425912467383","article-title":"NLRX1 does not inhibit MAVS-dependent antiviral signalling","volume":"19","author":"Soares","year":"2013","journal-title":"Innate Immun"},{"key":"B24","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.metabol.2017.04.008","article-title":"Acute detachment of hexokinase II from mitochondria modestly increases oxygen consumption of the intact mouse heart","volume":"72","author":"Nederlof","year":"2017","journal-title":"Metabolism"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvy089","article-title":"Increased cardiac fatty acid oxidation in a mouse model with decreased malonyl-CoA sensitivity of CPT1B","volume":"114","author":"van Weeghel","year":"2018","journal-title":"Cardiovasc Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00942.2003","article-title":"Profiling sunstrate fluxes in the isolated working mouse heart using 13C-labeled substrates: focusing on the origin and fate of pyruvate and citrate carbons","volume":"286","author":"Khairallah","year":"2004","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2013.09.014","article-title":"The heart is better protected against myocardial protection in the fed state compareed to the fasted state","volume":"63","author":"Liepinsh","year":"2014","journal-title":"Metabolism"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01182.2004","article-title":"Ischemic preconditioning, insulin, and morphine all cause hexokinase redistribution","volume":"289","author":"Zuurbier","year":"2005","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvz004","article-title":"Delayed ischaemic contracture onset by empagliflozin associates with NHE1 inhibition and is dependent on insulin in isolated mouse hearts","volume":"115","author":"Uthman","year":"2019","journal-title":"Cardiovasc Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"9562","DOI":"10.1038\/s41598-018-27875-3","article-title":"Pyruvate dehydrogenase complex plays a central role in brown adipocyte energy expenditure and fuel utilization during short-term beta-adrenergic activation","volume":"8","author":"Held","year":"2018","journal-title":"Sci Rep"},{"key":"B31","doi-asserted-by":"publisher","first-page":"17910","DOI":"10.1038\/s41598-018-36293-4","article-title":"Correcting for natural isotope abundance and tracer impurity in MS-, MS\/MS- and high-resolution-multiple-tracer-data from stable isotope labeling experiments with IsoCorrectoR","volume":"8","author":"Heinrich","year":"2018","journal-title":"Sci Rep"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.08.021","article-title":"Integrated, Step-Wise, Mass-Isotopomeric Flux Analysis of the TCA Cycle","volume":"22","author":"Alves","year":"2015","journal-title":"Cell Metab"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02419","article-title":"NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function","volume":"10","author":"Nagai-Singer","year":"2019","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900364","article-title":"Activation of NLRX1 by NX-13 Alleviates Inflammatory Bowel Disease through Immunometabolic Mechanisms in CD4(+) T Cells","volume":"203","author":"Leber","year":"2019","journal-title":"J Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2014.09.148","article-title":"Nlrp3 plays no role in acute cardiac infarction due to low cardiac expression","volume":"177","author":"Jong","year":"2014","journal-title":"Int J Cardiol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.116.305348","article-title":"Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning","volume":"116","author":"Heusch","year":"2015","journal-title":"Circ Res"},{"key":"B37","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s13045-018-0573-9","article-title":"NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells","volume":"11","author":"Hu","year":"2018","journal-title":"J Hematol Oncol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.02.065","article-title":"NLRX1 Acts as an Epithelial-Intrinsic Tumor Suppressor through the Modulation of TNF-Mediated Proliferation","volume":"14","author":"Tattoli","year":"2016","journal-title":"Cell Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00515.2019","article-title":"Carnitine palmitoyltrnasferase 2 knockout potentiates palmitate-induced insulin resistance in C2C12 myotubes","volume":"319","author":"Blackburn","year":"2020","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-255901","article-title":"Acylcarnitines: potential implications for skeletal muscle insulin resistance","volume":"29","author":"Aguer","year":"2015","journal-title":"FASEB J"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/biof.1378","article-title":"Acute and long-term administration of palmitoylcarnitine induced muscle-specific insulin resistance in mice","volume":"43","author":"Liepinsh","year":"2017","journal-title":"Biofactors"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601547","article-title":"NLRX1 Regulates Effector and Metabolic Functions of CD4(+) T Cells","volume":"198","author":"Leber","year":"2017","journal-title":"J Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.591815\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T00:33:37Z","timestamp":1607646817000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.591815\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,11]]},"references-count":42,"alternative-id":["10.3389\/fimmu.2020.591815"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2020.591815","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,11]]},"article-number":"591815"}}