Host-Pathogen Interactions Program, Texas Biomedical Research Institute, San Antonio, Texas, 78227, USA.
Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio, 43201, USA.
Adv Sci (Weinh). 2024 Feb;11(5):e2303664. doi: 10.1002/advs.202303664. Epub 2023 Nov 21.
Mitochondrial dysfunction alters cellular metabolism, increases tissue oxidative stress, and may be principal to the dysregulated signaling and function of CD4 T lymphocytes in the elderly. In this proof of principle study, it is investigated whether the transfer of functional mitochondria into CD4 T cells that are isolated from old mice (aged CD4 T cells), can abrogate aging-associated mitochondrial dysfunction, and improve the aged CD4 T cell functionality. The results show that the delivery of exogenous mitochondria to aged non-activated CD4 T cells led to significant mitochondrial proteome alterations highlighted by improved aerobic metabolism and decreased cellular mitoROS. Additionally, mito-transferred aged CD4 T cells showed improvements in activation-induced TCR-signaling kinetics displaying markers of activation (CD25), increased IL-2 production, enhanced proliferation ex vivo. Importantly, immune deficient mouse models (RAG-KO) showed that adoptive transfer of mito-transferred naive aged CD4 T cells, protected recipient mice from influenza A and Mycobacterium tuberculosis infections. These findings support mitochondria as targets of therapeutic intervention in aging.
线粒体功能障碍改变细胞代谢，增加组织氧化应激，可能是导致老年 CD4 T 淋巴细胞信号转导和功能失调的主要原因。在这项原理验证研究中，研究人员探讨了将功能正常的线粒体转移到从小鼠（老年 CD4 T 细胞）中分离出来的 CD4 T 细胞中，是否可以消除与衰老相关的线粒体功能障碍，并改善老年 CD4 T 细胞的功能。结果表明，将外源性线粒体递送到未激活的老年 CD4 T 细胞中，导致有氧代谢改善和细胞内线粒体 ROS 减少，线粒体蛋白质组发生显著变化。此外，转线粒体的老年 CD4 T 细胞在激活诱导的 TCR 信号转导动力学方面表现出激活标志物（CD25）的改善、IL-2 产生增加、体外增殖增强。重要的是，免疫缺陷小鼠模型（RAG-KO）表明，过继转移转线粒体的幼稚老年 CD4 T 细胞可保护受体小鼠免受流感 A 和结核分枝杆菌感染。这些发现支持将线粒体作为衰老治疗干预的靶点。
