Repurposing mitochondria from ATP production to ROS generation drives a pro-inflammatory phenotype in macrophages that depends on succinate oxidation by complex II

By E. Mills, B. Kelly, A. Logan, Ana S. H. Costa, M. Varma, C. Bryant, Panagiotis Tourlomousis, J. Däbritz, Eyal Gottlieb, I. Latorre and 10 more. Cell, 2016

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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 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.

Subfields: Immunology, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/46a8b25f1bda446e2e0026926f142954a42bc9a6

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Citations in the corpus

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “The NAD abundance as well as the NAD/NADH ratio, therefore, decline significantly even with the induction of the de novo synthesis from the KP in response to the lipopolysaccharide (LPS) challenge.(256,257) To maintain the cellular NAD level, NAD salvage enzyme NAMPT has been activated by LPS to boo”
Mitochondrial metabolism and cancer (2017, background): “A similar consideration applies to the pro-inflammatory activity of M1 macrophages, which relies on ROS-dependent NF-κB transcriptional responses as well as on the activation of the so-called inflammasome, a supramolecular platform that synthesizes IL1B and IL18 in a ROS- and mtDNA-dependent manner ”
The Metabolic Signature of Macrophage Responses (2019, background): “This associates to a significant release of ROS, which can activate HIF1α in M1 macrophages (65, 103).”