Elucidating the mitochondrial function of murine lymphocyte subsets and the heterogeneity of the mitophagy pathway inherited from hematopoietic stem cells.
Elucidating the mitochondrial function of murine lymphocyte subsets and the heterogeneity of the mitophagy pathway inherited from hematopoietic stem cells.
复制标题
阐明小鼠淋巴细胞亚群的线粒体功能以及从造血干细胞继承的线粒体自噬途径的异质性。
DOI：
10.3389/fimmu.2022.1061448
复制
发表时间：
2022
影响因子：
7.3
通讯作者：
Zhou, Yuan
中科院分区：
文献类型：
--
作者：
Liang, Haoyue;Fu, Weichao;Yu, Wenying;Cao, Zhijie;Liu, Ertao;Sun, Fanfan;Kong, Xiaodong;Gao, Yingdai;Zhou, Yuan
线粒体主要参与ATP的产生，以满足细胞的能量需求。线粒体在造血细胞分化和活化过程中的重要作用已被越来越多的研究者所认识，但线粒体代谢对不同分化和活化阶段淋巴细胞亚群的影响还有待研究。本研究比较了不同分化和活化阶段的淋巴细胞（包括CD 8 + T淋巴细胞、CD 4 + T淋巴细胞、B淋巴细胞、NK细胞及其亚群）的线粒体功能。为此，使用一套完整的方法来综合分析淋巴细胞亚群的线粒体自噬水平、线粒体活性氧（ROS）、线粒体膜电位（MMP）和线粒体质量（MM）。预计这将提供一套完整的标准，并绘制淋巴细胞亚群在不同分化和活化阶段的线粒体代谢图谱。在所有淋巴细胞中，B细胞具有相对较高的线粒体代谢活性，这从较高水平的线粒体自噬、ROS、MMP和MM中可以看出，这反映了淋巴细胞中线粒体代谢的高度异质性。在各B细胞亚群中，前B细胞的MM和MMP水平相对较高，而成熟B细胞的线粒体代谢水平相对较低。同样，在CD 4 + T细胞亚群中，幼稚CD 4 + T细胞的线粒体代谢水平相对较高。最后，从CD 8 + T细胞亚群中，CD 8 + Tcm具有相对较高的MM和MMP水平，但线粒体自噬水平相对较低，效应T细胞显示出相反的特征。同时，对造血干细胞、造血祖细胞和淋巴细胞亚群等淋巴系造血细胞的自噬相关基因进行分析，初步发现这些细胞在选择线粒体自噬相关的Pink 1/Park 2、BNIP 3/NIX和FUNDC 1通路时存在异质性。结果显示，与CD 4 + T、CD 8 + T和NK细胞相比，B细胞在参与Pink 1/Park 2通路方面与长期造血干细胞（LT-HSC）和短期造血干细胞（ST-HSC）更相似，自噬通路的特征在多大程度上遗传自HSC。与CLP和B细胞相比，HSC参与BNIP 3/NIX通路的程度较低。在B细胞亚群中，前B细胞较前B、未成熟B和未成熟B细胞在参与Pink 1/Park 2通路方面遗传了最少的HSC特征。在CD 4 + T细胞亚群中，nTreg细胞参与Pink 1/Park 2信号通路的能力较幼稚CD 4 + T细胞和记忆性CD 4 + T细胞弱。在CD 8 + T细胞亚群中，与CLP和效应CD 8 + T细胞相比，CD 8 + Tcm在参与Pink 1/Park 2通路方面继承了HSC的最少特征。CLP、初始CD 4 + T细胞和效应CD 8 + T细胞参与BNIP 3/NIX通路的程度高于其他淋巴造血细胞。本研究有望为今后研究淋巴细胞亚群在生理状态下分化活化不同阶段的线粒体功能提供一套完整的方法和基本参考值，也为基于线粒体代谢的感染和免疫研究提供标准和参考。
Mitochondria are mainly involved in ATP production to meet the energy demands of cells. Researchers are increasingly recognizing the important role of mitochondria in the differentiation and activation of hematopoietic cells, but research on how mitochondrial metabolism influence different subsets of lymphocyte at different stages of differentiation and activation are yet to be carried out. In this work, the mitochondrial functions of lymphocytes were compared at different differentiation and activation stages and included CD8+ T lymphocytes, CD4+ T lymphocytes, B lymphocytes, NK cells as well as their subsets. For this purpose, a complete set of methods was used to comprehensively analyze mitophagy levels, mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and the mitochondrial mass (MM) of subsets of lymphocytes. It is expected that this will provide a complete set of standards, and drawing the mitochondrial metabolic map of lymphocyte subsets at different stages of differentiation and activation. Of all lymphocytes, B cells had a relatively high mitochondrial metabolic activity which was evident from the higher levels of mitophagy, ROS, MMP and MM, and this reflected the highly heterogeneous nature of the mitochondrial metabolism in lymphocytes. Among the B cell subsets, pro-B cells had relatively higher levels of MM and MMP, while the mitochondrial metabolism level of mature B cells was relatively low. Similarly, among the subsets of CD4+ T cell, a relatively higher level of mitochondrial metabolism was noted for naive CD4+ T cells. Finally, from the CD8+ T cell subsets, CD8+ Tcm had relatively high levels of MM and MMP but relatively low ones for mitophagy, with effector T cells displaying the opposite characteristics. Meanwhile, the autophagy-related genes of lymphoid hematopoietic cells including hematopoietic stem cells, hematopoietic progenitor cells and lymphocyte subsets were analyzed, which preliminarily showed that these cells were heterogeneous in the selection of mitophagy related Pink1/Park2, BNIP3/NIX and FUNDC1 pathways. The results showed that compared with CD4+ T, CD8+ T and NK cells, B cells were more similar to long-term hematopoietic stem cell (LT-HSC) and short-term hematopoietic stem cell (ST-HSC) in terms of their participation in the Pink1/Park2 pathway, as well as the degree to which the characteristics of autophagy pathway were inherited from HSC. Compared with CLP and B cells, HSC are less involved in BNIP3/NIX pathway. Among the B cell subsets, pro-B cells inherited the least characteristics of HSC in participating in Pink1/Park2 pathway compared with pre-B, immature B and immature B cells. Among CD4+ T cell subsets, nTreg cells inherited the least characteristics of HSC in participating in Pink1/Park2 pathway compared with naive CD4+ T and memory CD4+ T cells. Among the CD8+ T cell subsets, compared with CLP and effector CD8+ T cells, CD8+ Tcm inherit the least characteristics of HSC in participating in Pink1/Park2 pathway. Meanwhile, CLP, naive CD4+ T and effector CD8+ T were more involved in BNIP3/NIX pathway than other lymphoid hematopoietic cells. This study is expected to provide a complete set of methods and basic reference values for future studies on the mitochondrial functions of lymphocyte subsets at different stages of differentiation and activation in physiological state, and also provides a standard and reference for the study of infection and immunity based on mitochondrial metabolism.
登录
查看更多内容
DOI：
10.1172/jci148546
发表时间：
2022-01-04
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Corrado M;Pearce EL
通讯作者：
Pearce EL
影响因子：
16.6
作者：
Jang, Kyoung-Jin;Mano, Hiroto;Aoki, Koji;Hayashi, Tatsunari;Muto, Akihiko;Nambu, Yukiko;Takahashi, Katsu;Itoh, Katsuhiko;Taketani, Shigeru;Nutt, Stephen L.;Igarashi, Kazuhiko;Shimizu, Akira;Sugai, Manabu
通讯作者：
Sugai, Manabu
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
7.4
作者：
Abimannan, Thiruvaimozhi;Peroumal, Doureradjou;Devadas, Satish
通讯作者：
Devadas, Satish
影响因子：
15.9
作者：
Gerriets, Valerie A.;Kishton, Rigel J.;Rathmell, Jeffrey C.
通讯作者：
Rathmell, Jeffrey C.