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
  • 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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