Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells

• DOI: 10.1016/j.celrep.2025.115430
• Publication Date: 2025-03-13T22:13:37Z
• Authors: Beibei Wu; Jin Seok Woo; Spyridon Hasiakos; Calvin Pan; Shawn Cokus; Cristiane Benincá; Linsey Stiles; Zuoming Sun; Matteo Pellegrini; Orian S. Shirihai; Aldon J. Lusis; Sonal Srikanth; Yousang Gwack

Genetic and environmental factors shape an individual's susceptibility to autoimmunity. To identify genetic variations regulating effector T cell functions, we used a forward genetics screen of inbred mouse strains uncovered genomic loci linked cytokine expression. Among the candidate genes, characterized mitochondrial inner membrane protein, TMEM11, as important determinant Th1 responses. Loss TMEM11 selectively impairs reducing autoimmune symptoms in mice. Mechanistically, Tmem11-/- cells exhibit altered cristae architecture, impaired respiration, increased reactive oxygen species (mtROS) production. Elevated mtROS hindered histone acetylation while promoting neutral lipid accumulation. Further experiments using genetic, biochemical, pharmacological tools revealed that regulate acetyl-CoA flux between fatty acid synthesis. Our findings highlight role integrity directing metabolic pathways influence chromatin modifications biosynthesis cells, providing new insights into immune metabolism.