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

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

SUBMITTER: Nuyttens L 

PROVIDER: S-EPMC12542566 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature