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- Title
Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8<sup>+</sup> T cell metabolic fitness and function in tumors.
- Authors
Yang, Jie-Feng; Xing, Xudong; Luo, Li; Zhou, Xin-Wei; Feng, Jian-Xiong; Huang, Kang-Bo; Liu, Huashan; Jin, Shanzhao; Liu, Yi-Na; Zhang, Shi-Hui; Pan, Yi-Hui; Yu, Bing; Yang, Jin-Yu; Cao, Yu-Lu; Cao, Yun; Yang, Cliff Y.; Wang, Yuan; Zhang, Yuxia; Li, Jiang; Xia, Xiaojun
- Abstract
Metabolic fitness of T cells is essential for their vitality, which is largely dependent on the behavior of the mitochondria. The nature of mitochondrial behavior in tumor-infiltrating T cells remains poorly understood. In this study, we show that mitofusin-2 (MFN2) expression is positively correlated with the prognosis of multiple cancers. Genetic ablation of Mfn2 in CD8+ T cells dampens mitochondrial metabolism and function and promotes tumor progression. In tumor-infiltrating CD8+ T cells, MFN2 enhances mitochondria–endoplasmic reticulum (ER) contact by interacting with ER-embedded Ca2+-ATPase SERCA2, facilitating the mitochondrial Ca2+ influx required for efficient mitochondrial metabolism. MFN2 stimulates the ER Ca2+ retrieval activity of SERCA2, thereby preventing excessive mitochondrial Ca2+ accumulation and apoptosis. Elevating mitochondria-ER contact by increasing MFN2 in CD8+ T cells improves the efficacy of cancer immunotherapy. Thus, we reveal a tethering-and-buffering mechanism of organelle cross-talk that regulates the metabolic fitness of tumor-infiltrating CD8+ T cells and highlights the therapeutic potential of enhancing MFN2 expression to optimize T cell function. Editor's summary: Organelle cross-talk plays a fundamental role in cell biology, but how this cross-talk controls tumor-infiltrating CD8+ T cells (TILs) is not understood. Yang et al. investigate the role of MFN2 in CD8+ TILs, identifying that mitochondrial interaction with the endoplasmic reticulum (ER) is required for metabolic fitness and antitumor activity. Through interaction with SERCA2 on the ER, MFN2 was required for mitochondria-ER contact and Ca2+ homeostasis. MFN2 expression was associated with better survival in patients with cancer, and promoting MFN2 expression in CD8+ T cells improved response to immune checkpoint blockade in mice. Together, these findings identify a critical role for MFN2 in regulating the metabolism, function, and survival of CD8+ T cells and suggest that boosting MFN2 expression is an attractive avenue for improving immunotherapy. —Hannah Isles
- Publication
Science Immunology, 2023, Vol 8, Issue 87, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.abq2424