Citrate – new functions for an old metabolite

Iacobazzi, Vito; Infantino, Vittoria

doi:10.1515/hsz-2013-0271

Cited by 226 publications

(196 citation statements)

References 96 publications

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“…Additional antihemostatic and anti-inflammatory activities of citrate may indirectly derive from its effects on blood cell components, including reduced activation of white blood cells and platelets (24)(25)(26)(27)(28)(29), and protective effects against endothelial-cell inflammation and dysfunction (30). Furthermore, citrate may be directly involved as a signal molecule in several cellular processes related to inflammation and balance of oxidative species (31). On this basis, citrate may behave as a true anti-inflammatory agent (10,18).…”

Section: Rca: Basic Principles and Citrate Metabolismmentioning

confidence: 99%

Regional Citrate Anticoagulation for RRTs in Critically Ill Patients with AKI

Morabito

Pistolesi

Tritapepe

et al. 2014

Clinical Journal of the American Society of Nephrology

124

130

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Hemorrhagic complications have been reported in up to 30% of critically ill patients with AKI undergoing RRT with systemic anticoagulation. Because bleeding is associated with significantly increased mortality risk, strategies aimed at reducing hemorrhagic complications while maintaining extracorporeal circulation should be implemented. Among the alternatives to systemic anticoagulation, regional citrate anticoagulation has been shown to prolong circuit life while reducing the incidence of hemorrhagic complications and lowering transfusion needs. For these reasons, the recently published Kidney Disease Improving Global Outcomes Clinical Practice Guidelines for Acute Kidney Injury have recommended regional citrate anticoagulation as the preferred anticoagulation modality for continuous RRT in critically ill patients in whom it is not contraindicated. However, the use of regional citrate anticoagulation is still limited because of concerns related to the risk of metabolic complications, the complexity of the proposed protocols, and the need for customized solutions. The introduction of simplified anticoagulation protocols based on citrate and the development of dialysis monitors with integrated infusion systems and dedicated software could lead to the wider use of regional citrate anticoagulation in upcoming years.

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Section: Rca: Basic Principles and Citrate Metabolismmentioning

confidence: 99%

Regional Citrate Anticoagulation for RRTs in Critically Ill Patients with AKI

Morabito

Pistolesi

Tritapepe

et al. 2014

Clinical Journal of the American Society of Nephrology

124

130

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“…Numerous studies have demonstrated that the use of glycolysis and the tricarboxylic acid (TCA) 2 cycle intermediates for biosynthesis is a key feature of altered metabolism in cancer cells (6,7). Among others, citrate, an intermediate metabolite located at the crossroads of glucose metabolism and energy production, is an important sensor of energy homeostasis (8).…”

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confidence: 99%

Silencing of solute carrier family 13 member 5 disrupts energy homeostasis and inhibits proliferation of human hepatocarcinoma cells

Choi

et al. 2017

Journal of Biological Chemistry

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The solute carrier family 13 member 5 (SLC13A5), a sodiumcoupled citrate transporter, plays a key role in importing citrate from the circulation into liver cells. Recent evidence has revealed that SLC13A5 deletion protects mice from high-fat diet-induced hepatic steatosis and that mutation of the SLC13A5 orthologues in Drosophila melanogaster and Caenorhabditis elegans promotes longevity. However, despite the emerging importance of SLC13A5 in energy homeostasis, whether perturbation of SLC13A5 affects the metabolism and malignancy of hepatocellular carcinoma is unknown. Here, we sought to determine whether SLC13A5 regulates hepatic energy homeostasis and proliferation of hepatoma cells. RNAi-mediated silencing of SLC13A5 expression in two human hepatoma cell lines, HepG2 and Huh7, profoundly suppressed cell proliferation and colony formation, and induced cell cycle arrest accompanied by increased expression of cyclin-dependent kinase inhibitor p21 and decreased expression of cyclin B1. Furthermore, such suppressive effects were also observed on the growth of HepG2 cell-derived xenografts expressing SLC13A5-shRNA in nude mice. Metabolically, knockdown of SLC13A5 in HepG2 and Huh7 cells was associated with a decrease in intracellular levels of citrate, the ratio of ATP/ADP, phospholipid content, and ATP citrate lyase expression. Moreover, both in vitro and in vivo assays demonstrated that SLC13A5 depletion promotes activation of the AMP-activated protein kinase, which was accompanied by deactivation of oncogenic mechanistic target of rapamycin signaling. Together, our findings expand the role of SLC13A5 from facilitating hepatic energy homeostasis to influencing hepatoma cell proliferation and suggest a potential role of SLC13A5 in the progression of human hepatocellular carcinoma.Metabolic reprogramming has long been regarded as a hallmark of cancer, through which cancer cells switch from oxidative phosphorylation to glycolysis for ATP production even in microenvironments with sufficient oxygen (1, 2). To accommodate the challenge of rapid proliferation, cancer cell metabolism is remodeled to increase the biosynthesis of macromolecules including nucleotides, proteins, and lipids as building blocks of new cells (3,4). Although the precise mechanisms underlying this metabolic reprogramming remain elusive, malignant cells often have perturbed metabolism that allows for the accumulation of many metabolic intermediates facilitating the production of cellular building materials (4,5). Numerous studies have demonstrated that the use of glycolysis and the tricarboxylic acid (TCA) 2 cycle intermediates for biosynthesis is a key feature of altered metabolism in cancer cells (6, 7). Among others, citrate, an intermediate metabolite located at the crossroads of glucose metabolism and energy production, is an important sensor of energy homeostasis (8).Accumulating evidence suggests that citrate is involved in both physiological and pathophysiological processes including histone acetylation, insulin secretion, inflammation, ca...

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“…The citrate carrier catalyses the transport of citrate, a product of tricarboxylate (TCA) cycle, out of the mitochondrion in exchange for malate, a process that profoundly influences energy balance in the cells (Bisaccia et al, 1989Kaplan et al, 1993;Iacobazzi and Infantino, 2014;Kolukula et al, 2014). In the cytosol, citrate is cleaved by ATP-citrate lyase to oxaloacetate and acetylCoA.…”

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%

“…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%

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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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Citrate – new functions for an old metabolite

Cited by 226 publications

References 96 publications

Regional Citrate Anticoagulation for RRTs in Critically Ill Patients with AKI

Regional Citrate Anticoagulation for RRTs in Critically Ill Patients with AKI

Silencing of solute carrier family 13 member 5 disrupts energy homeostasis and inhibits proliferation of human hepatocarcinoma cells

Mitochondrial carriers in inflammation induced by bacterial endotoxin and cytokines

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