RNA seq analysis of liver tissue from wild-type mice exposed to CS versus vehicle

ABSTRACT: Sepsis is a life-threatening dysregulated host response to infection that drives hepatic failure through ischemia, metabolic inflexibility, and bioenergetic collapse. The ionic and metabolic circuitry linking inflammatory stress to mitochondrial energetic collapse, however, remains unresolved. Using a murine cecal slurry model, we integrated transcriptomics, untargeted metabolomics, and real-time single-cell imaging to delineate the intracellular Mg²⁺ dynamics-driven metabolic remodeling that underlies septic liver dysfunction. Transcriptomic profiling revealed robust activation of HIF1α-driven glycolysis coupled with coordinated repression of mitochondrial genes governing the tricarboxylic acid cycle and oxidative phosphorylation complexes. In parallel, untargeted metabolomics demonstrated marked accumulation of glycolytic intermediates, including lactate, glyceraldehyde 3 phosphate, and dihydroxyacetone phosphate, accompanied by profound reduction of TCA cycle intermediates and cofactors, indicating severe mitochondrial energetic failure. Mechanistically, we show that accumulated glycolytic intermediates trigger Mg²⁺ mobilization from the endoplasmic reticulum into the mitochondrial matrix via the inner membrane Mg²⁺ selective channel MRS2. Biosensor-based measurements confirm that inflammatory stimuli such as LPS amplify glycolytic output while suppressing mitochondrial citrate production, reinforcing a shift toward glycolysis-driven Mg²⁺ signaling. During sepsis, MRS2-mediated mMg²⁺ overload dampens mitochondrial respiration, while the genetic ablation of Mrs2 limits the mMg²⁺ elevation and preserves mitochondrial function comparable to normal hepatocytes. These findings define a previously unrecognized Mg²⁺-regulated metabolic axis in sepsis, wherein HIF1α-driven glycolysis engages MRS2-dependent mMg²⁺ uptake to restrict oxidative metabolism. By repositioning MRS2 and Mg²⁺ handling pathways as central determinants of septic bioenergetics, this work identifies molecular targets for restoring mitochondrial function and preventing organ failure in sepsis.

ORGANISM(S): Mus musculus

PROVIDER: GSE315992 | GEO | 2026/03/31

REPOSITORIES: GEO