Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages

Mills, E. L. et al. (2016) Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell, 167(2), 457-470.e13. (doi: 10.1016/j.cell.2016.08.064) (PMID:27667687)

Abstract

Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Däbritz, Jan and Gottlieb, Professor Eyal
• Authors: Mills, E. L., Kelly, B., Logan, A., Costa, A. S.H., Varma, M., Bryant, C. E., Tourlomousis, P., Däbritz, J. H. M., Gottlieb, E., Latorre, I., Corr, S. C., McManus, G., Ryan, D., Jacobs, H. T., Szibor, M., Xavier, R. J., Braun, T., Frezza, C., Murphy, M. P., and O’Neill, L. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell
• Publisher: Elsevier (Cell Press)
• ISSN: 0092-8674
• ISSN (Online): 1097-4172
• Published Online: 22 September 2016
• Copyright Holders: Copyright © 2016 Crown Copyright
• First Published: First published in Cell 167(2): 457-470.e13
• Publisher Policy: Reproduced in accordance with the publisher copyright policy