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

Mistry, Jayna J., Marlein, Christopher R., Moore, Jamie A., Hellmich, Charlotte, Wojtowicz, Edyta E., Smith, James G. W. ORCID: https://orcid.org/0000-0003-0427-8678, Macaulay, Iain, Sun, Yu, Morfakis, Adam, Patterson, Angela, Horton, Rebecca H., Divekar, Devina, Morris, Christopher J. ORCID: https://orcid.org/0000-0002-7703-4474, Haestier, Anna, Di Palma, Federica, Beraza, Naiara, Bowles, Kristian M. ORCID: https://orcid.org/0000-0003-1334-4526 and Rushworth, Stuart A. (2019) ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection. Proceedings of the National Academy of Sciences of the United States of America, 116 (49). pp. 24610-24619. ISSN 1091-6490

Preview	PDF (Published_Version) - Published Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (1MB) | Preview
Preview	PDF (Published_Version) - Published Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (1MB) | Preview

Abstract

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.

Item Type:	Article
Additional Information:	Copyright © 2019 the Author(s). Published by PNAS.
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science > School of Biological Sciences Faculty of Science > School of Pharmacy
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Cardiovascular and Metabolic Health Faculty of Science > Research Groups > Pharmaceutical Materials and Soft Matter Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	15 Nov 2019 09:30
Last Modified:	25 Oct 2023 01:01
URI:	https://ueaeprints.uea.ac.uk/id/eprint/72969
DOI:	10.1073/pnas.1913278116

Downloads

Actions (login required)

View Item