ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection

Jayna J. Mistry, Christopher R. Marlein, Jamie A. Moore, Charlotte Hellmich, Edyta E. Wojtowicz, James G. W. Smith, Iain Macaulay, Yu Sun, Adam Morfakis, Angela Patterson, Rebecca H. Horton, Devina Divekar, Christopher J. Morris, Anna Haestier, Federica Di Palma, Naiara Beraza, Kristian M. Bowles, Stuart A. Rushworth

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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.

Original languageEnglish
Pages (from-to)24610-24619
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number49
Early online date14 Nov 2019
Publication statusPublished - 3 Dec 2019

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