AUTHOR=Nuyttens Louise , Heyerick Marah , Roes Maxime , Moens Elise , Van Dender Céline , Wallaeys Charlotte , Hochepied Tino , Timmermans Steven , Vandewalle Jolien , Libert Claude 

TITLE=A crucial role of the malate aspartate shuttle in metabolic reprogramming in TNF-induced SIRS

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1652516

DOI=10.3389/fimmu.2025.1652516

ISSN=1664-3224

ABSTRACT=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+. This downregulation of MAS genes in TNF-induced SIRS likely results from loss of HNF4α function, which appears to be the key transcription factor involved. Using Slc25a13-/- mice lacking citrin – a crucial MAS component – we demonstrate that MAS dysfunction exacerbates TNF-induced metabolic dysregulations and lethality. Disruptive NAD+ regeneration leads to diminished mitochondrial β-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.