ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection
ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection
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DOI：
10.1073/pnas.1913278116
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发表时间：
2019-12-03
影响因子：
11.1
通讯作者：
Rushworth, Stuart A.
中科院分区：
文献类型：
--
作者：
Mistry, Jayna J.;Marlein, Christopher R.;Rushworth, Stuart A.
造血干细胞（hsc）在应激刺激下快速扩增。在这里，我们研究了促进HSC在感染反应中扩增的生物能量过程。我们发现革兰氏阴性菌感染会导致哺乳动物造血干细胞线粒体质量增加，从而导致糖酵解向氧化磷酸化的代谢转变。线粒体质量的最初增加是由于线粒体通过依赖活性氧（ROS）的机制从骨髓基质细胞（BMSCs）转移到造血干细胞。从机制上讲，ros诱导的氧化应激调节了由磷酸肌肽3激酶（PI3K）激活介导的系统中连接蛋白通道的打开，从而允许线粒体从骨髓间充质干细胞转移到造血干细胞。此外，在对细菌感染的反应中，线粒体从骨髓间充质干细胞转移到造血干细胞，发生在造血干细胞激活其自身的线粒体生物发生转录程序之前。我们的发现表明，线粒体从骨髓微环境转移到造血干细胞是哺乳动物对急性细菌感染反应的早期生理事件，并导致支持紧急粒细胞生成的生物能量变化。
Hematopoietic stem cells (HSCs) undergo rapid expansion in response to stress stimuli. Here we investigate the bioenergetic processes which facilitate the HSC expansion in response to infection. We find that infection by Gram-negative bacteria drives an increase in mitochondrial mass in mammalian HSCs, which results in a metabolic transition from glycolysis toward oxidative phosphorylation. The initial increase in mitochondrial mass occurs as a result of mitochondrial transfer from the bone marrow stromal cells (BMSCs) to HSCs through a reactive oxygen species (ROS)-dependent mechanism. Mechanistically, ROS-induced oxidative stress regulates the opening of connexin channels in a system mediated by phosphoinositide 3-kinase (PI3K) activation, which allows the mitochondria to transfer from BMSCs into HSCs. Moreover, mitochondria transfer from BMSCs into HSCs, in the response to bacterial infection, occurs before the HSCs activate their own transcriptional program for mitochondrial biogenesis. Our discovery demonstrates that mitochondrial transfer from the bone marrow microenvironment to HSCs is an early physiologic event in the mammalian response to acute bacterial infection and results in bioenergetic changes which underpin emergency granulopoiesis.