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

• Published in: Cell reports (Cambridge) Vol. 44; no. 3; p. 115430
• Main Authors: Wu, Beibei, Woo, Jin Seok, Hasiakos, Spyridon, Pan, Calvin, Cokus, Shawn, Benincá, Cristiane, Stiles, Linsey, Sun, Zuoming, Pellegrini, Matteo, Shirihai, Orian S., Lusis, Aldon J., Srikanth, Sonal, Gwack, Yousang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.03.2025
• Subjects: Acetyl Coenzyme A - metabolism; Acetylation; Animals; cytokine production; Cytokines - biosynthesis; Cytokines - metabolism; EAE; Fatty Acids - biosynthesis; histone acetylation; Histones - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; MICOS complex; mitochondria; Mitochondria - metabolism; mitochondrial cristae architecture; neutral lipids; reactive oxygen species; Reactive Oxygen Species - metabolism; Th1 cells; Th1 Cells - immunology; Th1 Cells - metabolism; CP: Immunology; cytokine production; Th1 cells; CP: Metabolism; mitochondria; reactive oxygen species; EAE; MICOS complex; mitochondrial cristae architecture; histone acetylation; neutral lipids
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2025.115430

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 and uncovered genomic loci linked to cytokine expression. Among the candidate genes, we characterized a mitochondrial inner membrane protein, TMEM11, as an important determinant of Th1 responses. Loss of TMEM11 selectively impairs Th1 cell functions, reducing autoimmune symptoms in mice. Mechanistically, Tmem11−/− Th1 cells exhibit altered cristae architecture, impaired respiration, and increased mitochondrial reactive oxygen species (mtROS) production. Elevated mtROS hindered histone acetylation while promoting neutral lipid accumulation. Further experiments using genetic, biochemical, and pharmacological tools revealed that mtROS regulate acetyl-CoA flux between histone acetylation and fatty acid synthesis. Our findings highlight the role of mitochondrial cristae integrity in directing metabolic pathways that influence chromatin modifications and lipid biosynthesis in Th1 cells, providing new insights into immune cell metabolism. [Display omitted] •A mitochondrial inner membrane protein, TMEM11, regulates Th1 responses•Tmem11−/− Th1 cells show altered mitochondrial cristae morphology and high mtROS•Increased mtROS impaired histone acetylation and enhanced fatty acid synthesis•Cristae integrity can influence cellular metabolism and chromatin modification Using a forward genetics screen, Wu et al. uncovered the role of an inner mitochondrial membrane protein, TMEM11, in regulating Th1 cell effector functions. Tmem11−/− Th1 cells show alterations in mitochondrial cristae integrity and increased mtROS levels that influence cellular metabolism and chromatin modifications, resulting in decreased effector functions.