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Updated: May 1, 2026

Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells
Published on: March 28, 2025
Necrosis-driven systemic immune response alters SAM metabolism through the FOXO-GNMT axis
Fumiaki Obata1, Erina Kuranaga2, Katsura Tomioka3
1Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan.
Abstract:
Sterile inflammation triggered by endogenous factors is thought to contribute to the pathogenesis of acute and chronic inflammatory diseases. Here, we demonstrate that apoptosis-deficient mutants spontaneously develop a necrosis-driven systemic immune response in Drosophila and provide an in vivo model for studying the organismal response to sterile inflammation. Metabolomic analysis of hemolymph from apoptosis-deficient mutants revealed increased sarcosine and reduced S-adenosyl-methionine (SAM) levels due to glycine N-methyltransferase (Gnmt) upregulation. We showed that Gnmt was elevated in response to Toll activation induced by the local necrosis of wing epidermal cells. Necrosis-driven inflammatory conditions induced dFoxO hyperactivation, leading to an energy-wasting phenotype. Gnmt was cell-autonomously upregulated by dFoxO in the fat body as a possible rheostat for controlling energy loss, which functioned during fasting as well as inflammatory conditions. We propose that the dFoxO-Gnmt axis is essential for the maintenance of organismal SAM metabolism and energy homeostasis.
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