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  Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages

Mills, E. L., Kelly, B., Logan, A., Costa, A. S. H., Varma, M., Bryant, C. E., et al. (2016). Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages. CELL, 167(2), 457-+. doi:10.1016/j.cell.2016.08.064.

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Genre: Journal Article

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 Creators:
Mills, Evanna L., Author
Kelly, Beth, Author
Logan, Angela, Author
Costa, Ana S. H., Author
Varma, Mukund, Author
Bryant, Clare E., Author
Tourlomousis, Panagiotis, Author
Dabritz, J. Henry M., Author
Gottlieb, Eyal, Author
Latorre, Isabel, Author
Corr, Sinead C., Author
McManus, Gavin, Author
Ryan, Dylan, Author
Jacobs, Howard T., Author
Szibor, Marten1, Author              
Xavier, Ramnik J., Author
Braun, Thomas1, Author              
Frezza, Christian, Author
Murphy, Michael P., Author
O'Neill, Luke A., Author
Affiliations:
1Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

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Free keywords: INTERLEUKIN-10 IL-10; ELECTRON-TRANSPORT; REPERFUSION INJURY; DIMETHYL FUMARATE; RESPIRATORY-CHAIN; CELL-ACTIVATION; DENDRITIC CELL; IL-1-BETA; HYPOXIA; ALPHABiochemistry & Molecular Biology; Cell Biology;
 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.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: 27
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: CELL
Source Genre: Journal
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Publ. Info: 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA : CELL PRESS
Pages: - Volume / Issue: 167 (2) Sequence Number: - Start / End Page: 457 - + Identifier: ISSN: 0092-8674