The mitochondrial citrate carrier: a new player in inflammation

Infantino, Vittoria; Convertini, Paolo; Cucci, Liana; Panaro, Maria Antonietta; Noia, Maria Antonietta Di; Calvello, Rosa; Palmieri, Ferdinando; Iacobazzi, Vito

doi:10.1042/bj20111275

Cited by 327 publications

(308 citation statements)

References 24 publications

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“…This finding suggests that the transport of particular mediators from the mitochondria to the cytosol is required following LPS stimulation in macrophages. Among the various metabolic transporters, the mitochondrial citrate carrier (CIC) was found to be increased following LPS stimulation [10], probably due to activation of one or both of the two nuclear factor kB (NF-kB) sites contained in the CIC promoter. Furthermore, knockdown of CIC with small interfering RNA (siRNA), or by the use of an inhibitor, benzene-1,2,3-tricarboxylate, impaired the production of reactive oxygen species (ROS), nitric oxide (NO), and prostaglandins (PGs) in macrophages treated with LPS, suggesting that CIC is required for the induction of these mediators.…”

Section: Citrate Transportation Regulates Inflammatory Responsesmentioning

confidence: 99%

mentioning

confidence: 99%

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Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

553

445

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Succinate is an intermediate of the tricarboxylic acid (TCA) cycle, and plays a crucial role in adenosine triphosphate (ATP) generation in mitochondria. Recently, new roles for succinate outside metabolism have emerged. Succinate stabilizes the transcription factor hypoxia-inducible factor-1a (HIF-1a) in specific tumors and in activated macrophages, and stimulates dendritic cells via its receptor succinate receptor 1. Furthermore, succinate has been shown to post-translationally modify proteins. This expanding repertoire of functions for succinate suggests a broader role in cellular activation. We review the new roles of succinate and draw parallels to other metabolites such as NAD + and citrate whose roles have expanded beyond metabolism and into signaling. Metabolic alterations influence the immune responseThe immune system acts as an internal shield defending against invading pathogens and is made up of an innate system, including macrophages, neutrophils, and dendritic cells (DCs), and an adaptive system composed of T and B lymphocytes. Cells of the innate immune system recognize pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), present on their cell surface and in the cytosol [1]. Once activated, innate immune cells can initiate adaptive immunity to fight infection further and to generate immunological memory. In resting conditions these cells are relatively inactive; however, upon recognition of foreign material they have the ability to respond rapidly, producing a wide array of mediators such as cytokines, chemokines, and antimicrobial peptides to clear the infection.Such rapid induction of immunity represents a significant metabolic demand. In recent years it has become evident that immune cells have the ability to shift their metabolism under varying conditions and that this is essential for proper immune function [2]. Stimulation of DCs and macrophages can result in a decrease in oxidative phosphorylation, which is normally employed under resting conditions, with a concomitant increase in glycolysis and the pentose-phosphate pathway [3,4]. This switch to glycolysis rapidly generates ATP to maintain mitochondrial membrane potential and energy homeostasis, ultimately ensuring cell viability [5]. It also provides biosynthetic precursors required for proliferating cells and for cells with a prodigious biosynthetic capacity, such as macrophages when they are activated to produce cytokines. This altered metabolism is similar to the Warburg effect (aerobic glycolysis) observed in tumor cells [6] (Figure 1, Box 1). Indeed, the metabolic sensor HIF-1a can determine the growth and fate of both tumor cells and immune cells. For example, HIF-1a activation favors differentiation of T lymphocytes into proinflammatory Th17 cells and attenuates regulatory T cell development [7]. Importantly, as well as global changes in metabolism that occur in activated immune cells, individual metabolites, including succinate, citrate, and NAD + , have been d...

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Section: Citrate Transportation Regulates Inflammatory Responsesmentioning

confidence: 99%

mentioning

confidence: 99%

Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

553

445

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“…Transport of citrate via the CIC and citrate metabolism appear to be critical for the activation of macrophages (Infantino et al, 2011b;Iacobazzi and Infantino, 2014). In LPS-activated macrophages expression of the SLC25A1 gene is induced at the transcriptional level by two pro-inflammatory cytokines, tumour necrosis factor-α (TNFα) and interferon-γ (IFNγ), through NF-kB and STAT1 transcription factors, respectively (Figure 1).…”

Section: The Citrate Carrier Cic (Slc25a1)mentioning

confidence: 99%

“…The CIC is the most studied mitochondrial carrier in inflammation (Infantino et al, 2011bIacobazzi and Infantino, 2014;Palmieri et al, 2015). Transport of citrate via the CIC and citrate metabolism appear to be critical for the activation of macrophages (Infantino et al, 2011b;Iacobazzi and Infantino, 2014).…”

Section: The Citrate Carrier Cic (Slc25a1)mentioning

confidence: 99%

“…In a study performed on LPS-activated macrophages and U937 cells expression of the mitochondrial citrate carrier (SLC25A1) increases via NF-kB and STAT1 giving rise to increased levels of citrate in the cytosol . Here citrate is used to produce pro-inflammatory mediators, ROS, NO and prostaglandins (Infantino et al, 2011b). Succinate, another mitochondrial metabolite transported by the dicarboxylate carrier (SLC25A10), has been found to be a signal that induces IL-1β via HIF-1α (Tannahill et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial carriers in inflammation induced by bacterial endotoxin and cytokines

Iacobazzi

Infantino

Castegna

et al. 2016

Biological Chemistry

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Significant metabolic changes occur in the shift from resting to activated cellular status in inflammation. Thus, changes in expression of a large number of genes and extensive metabolic reprogramming gives rise to acquisition of new functions (e.g. production of cytokines, intermediates for biosynthesis, lipid mediators, PGE, ROS and NO). In this context, mitochondrial carriers, which catalyse the transport of solute across mitochondrial membrane, change their expression to transport mitochondrially produced molecules, among which citrate and succinate, to be used as intracellular signalling molecules in inflammation. This review summarises the mitochondrial carriers studied so far that are, directly or indirectly, involved in inflammation.

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Krebs cycle rewired for macrophage and dendritic cell effector functions

2017

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Edited by Laszlo NagyThe Krebs cycle is an amphibolic pathway operating in the mitochondrial matrix of all eukaryotic organisms. In response to proinflammatory stimuli, macrophages and dendritic cells undergo profound metabolic remodelling to support the biosynthetic and bioenergetic requirements of the cell. Recently, it has been discovered that this metabolic shift also involves the rewiring of the Krebs cycle to regulate cellular metabolic flux and the accumulation of Krebs cycle intermediates, notably, citrate, succinate and fumarate. Interestingly, a new role for Krebs cycle intermediates as signalling molecules and immunomodulators that dictate the inflammatory response has begun to emerge. This review will discuss the latest developments in Krebs cycle rewiring and immune cell effector functions, with a particular focus on the regulation of cytokine production.

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The mitochondrial citrate carrier: a new player in inflammation

Cited by 327 publications

References 24 publications

Succinate: a metabolic signal in inflammation

Succinate: a metabolic signal in inflammation

Mitochondrial carriers in inflammation induced by bacterial endotoxin and cytokines

Krebs cycle rewired for macrophage and dendritic cell effector functions

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