2. Academic Validation
  3. Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8+ T cell metabolic fitness and function in tumors

Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8+ T cell metabolic fitness and function in tumors

  • Sci Immunol. 2023 Sep 29;8(87):eabq2424. doi: 10.1126/sciimmunol.abq2424.
Jie-Feng Yang 1,  Xudong Xing 2,  Li Luo 1,  Xin-Wei Zhou 3,  Jian-Xiong Feng 1,  Kang-Bo Huang 1,  Huashan Liu 4,  Shanzhao Jin 2,  Yi-Na Liu 1,  Shi-Hui Zhang 1,  Yi-Hui Pan 3,  Bing Yu 1,  Jin-Yu Yang 1,  Yu-Lu Cao 1,  Yun Cao 1 5,  Cliff Y Yang 6,  Yuan Wang 7,  Yuxia Zhang 8 9,  Jiang Li 1,  Xiaojun Xia 1,  Tiebang Kang 1,  Rui-Hua Xu 1,  Ping Lan 4,  Jun-Hang Luo 3,  Hui Han 1,  Fan Bai 2,  Song Gao 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 2 Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics (ICG), School of Life Sciences, Peking University, Beijing 100871, China.
  • 3 Department of Urology, First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan Road II, Guangzhou 510080, China.
  • 4 Department of Colorectal Surgery, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
  • 5 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 6 Department of Immunology, Sun Yat-sen University, Zhongshan School of Medicine, Guangzhou 510080, China.
  • 7 Department of Animal Sciences, College of Agriculture and Natural Resources, Michigan State University, East Lansing, MI 48824, USA.
  • 8 Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
  • 9 Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
PMID: 37738362 DOI: 10.1126/sciimmunol.abq2424
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.

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