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

被引：0

作者：

Wu, Beibei ^{[1
]}

Woo, Jin Seok ^{[2
,10
]}

Hasiakos, Spyridon ^{[1
,2
]}

Pan, Calvin ^{[3
]}

Cokus, Shawn ^{[4
]}

Beninca, Cristiane ^{[5
,6
]}

Stiles, Linsey ^{[5
,6
,7
]}

Sun, Zuoming ^{[8
]}

Pellegrini, Matteo ^{[4
]}

Shirihai, Orian S. ^{[5
,6
,7
,9
]}

Lusis, Aldon J. ^{[3
]}

Srikanth, Sonal ^{[1
]}

Gwack, Yousang ^{[1
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA

[2] UCLA, Sch Dent, Div Oral Biol & Med, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Cardiol, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Endocrinol, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Metab Theme, Los Angeles, CA 90095 USA

[7] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA USA

[8] Beckman Res Inst City Hope, Arthur Riggs Diabet & Metab Res Inst, Dept Immunol & Theranost, Duarte, CA 91010 USA

[9] Univ Calif Los Angeles, Mol Cellular Integrat Physiol, Los Angeles, CA 90095 USA

[10] Catholic Univ Korea, Catholic Res Inst Med Sci, Rheumatism Res Ctr, Seoul 06591, South Korea

来源：

CELL REPORTS | 2025年 / 44卷 / 03期

关键词：

ATP CITRATE LYASE; INFLAMMATION; MORPHOLOGY; FUSION; GROWTH; ROS;

D O I：

10.1016/j.celrep.2025.115430

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：22

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