Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8 <sup>+</sup> T cell metabolic fitness and function in tumors
Jiefeng Yang, Jiefeng Yang, Xudong Xing, Li Luo, Xinwei Zhou, Jian-Xiong Feng, Kangbo Huang, Huashan Liu, Shanzhao Jin, Yina Liu, Shi-Hui Zhang, Yihui Pan, Bing Yu, Jinyu Yang, Jinyu Yang, Yu-Lu Cao, Yun Cao, Cliff Y. Yang, Yuan Wang, Yuxia Zhang, Jiang Li, Xiaojun Xia, Tiebang Kang, Rui‐Hua Xu, Ping Lan, Junhang Luo, Hui Han, Fan Bai, Song Gao
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 Ca 2+ -ATPase SERCA2, facilitating the mitochondrial Ca 2+ influx required for efficient mitochondrial metabolism. MFN2 stimulates the ER Ca 2+ retrieval activity of SERCA2, thereby preventing excessive mitochondrial Ca 2+ 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.