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

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.