{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T22:41:21Z","timestamp":1783464081090,"version":"3.55.0"},"reference-count":102,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Tumor necrosis factor (TNF) causes a lethal systemic inflammatory response syndrome (SIRS) which is characterized by significant metabolic alterations. Based on liver RNA sequencing, we found that TNF impairs the malate-aspartate shuttle (MAS), an essential redox shuttle that transfers reducing equivalents across the inner mitochondrial membrane thereby recycling cytosolic NAD\n                    <jats:sup>+<\/jats:sup>\n                    . This downregulation of MAS genes in TNF-induced SIRS likely results from loss of HNF4\u03b1 function, which appears to be the key transcription factor involved. Using Slc25a13\n                    <jats:sup>-\/-<\/jats:sup>\n                    mice lacking citrin \u2013 a crucial MAS component \u2013 we demonstrate that MAS dysfunction exacerbates TNF-induced metabolic dysregulations and lethality. Disruptive NAD\n                    <jats:sup>+<\/jats:sup>\n                    regeneration leads to diminished mitochondrial \u03b2-oxidation, leading to elevated levels of circulating free fatty acids (FFAs) and to hepatic lipid accumulation. Simultaneously, MAS dysfunction promotes glycolysis coupled to lactate production and reduces lactate-mediated gluconeogenesis, culminating in severe hyperlactatemia that triggers VEGF-induced vascular leakage. Overall, MAS dysfunction contributes to metabolic failure and lethality in TNF-induced SIRS, highlighting its potential as a promising, therapeutic target.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2025.1652516","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T05:40:03Z","timestamp":1759902003000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["A crucial role of the malate aspartate shuttle in metabolic reprogramming in TNF-induced SIRS"],"prefix":"10.3389","volume":"16","author":[{"given":"Louise","family":"Nuyttens","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marah","family":"Heyerick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime","family":"Roes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Moens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Van Dender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Wallaeys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tino","family":"Hochepied","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Timmermans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien","family":"Vandewalle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Libert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.CRJ06010X","article-title":"Systemic inflammatory response syndrome (SIRS): Molecular pathophysiology and gene therapy","volume":"101","author":"Matsuda","year":"2006","journal-title":"J Pharmacol Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA - 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