Blockage of citrate export prevents TCA cycle fragmentation via Irg1 inactivation

Li, Yang; Li, Yuchen; Liu, Xiaotian; Zhang, Lu; Chen, Yihua; Zhao, Qiong; Gao, Wen; Liu, Baolin; Yang, Hua; Li, Ping

doi:10.1016/j.celrep.2022.110391

Cited by 49 publications

(34 citation statements)

References 56 publications

(84 reference statements)

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“…Itaconate plays a critical role in metabolic and functional reprogramming in inflammatory diseases, with antimicrobial, antiviral, anti-inflammatory, metabolic, and other immunomodulatory effects [ 41 , 42 , 43 , 44 , 45 , 46 ]. CTP facilitates citrate transport to the cytosol and impaired CTP activity influences itaconate levels and histone acetylation [ 47 ]. CTP has been identified in vitro as a mitochondrial transporter of itaconate [ 48 ] further highlighting the impact of citrate on immune metabolism.…”

Section: Citrate Metabolism and Nactmentioning

confidence: 99%

Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5

2023

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The small molecule citrate is a key molecule that is synthesized de novo and involved in diverse biochemical pathways influencing cell metabolism and function. Citrate is highly abundant in the circulation, and cells take up extracellular citrate via the sodium-dependent plasma membrane transporter NaCT encoded by the SLC13A5 gene. Citrate is critical to maintaining metabolic homeostasis and impaired NaCT activity is implicated in metabolic disorders. Though citrate is one of the best known and most studied metabolites in humans, little is known about the consequences of altered citrate uptake and metabolism. Here, we review recent findings on SLC13A5, NaCT, and citrate metabolism and discuss the effects on metabolic homeostasis and SLC13A5-dependent phenotypes. We discuss the “multiple-hit theory” and how stress factors induce metabolic reprogramming that may synergize with impaired NaCT activity to alter cell fate and function. Furthermore, we underline how citrate metabolism and compartmentalization can be quantified by combining mass spectrometry and tracing approaches. We also discuss species-specific differences and potential therapeutic implications of SLC13A5 and NaCT. Understanding the synergistic impact of multiple stress factors on citrate metabolism may help to decipher the disease mechanisms associated with SLC13A5 citrate transport disorders.

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Section: Citrate Metabolism and Nactmentioning

confidence: 99%

Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5

2023

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“…Surprisingly, we did not find differences in the expression of cholesterol handling or efflux genes observed in BMDMs, which may be due to interspecies or cell line differences. In contrast to the phenotype of ACLY-deficient THP-1 cells or murine macrophages, studies using pharmacological inhibition or silencing of ACLY showed suppressed responses towards LPS stimulation linked to gene-specific inhibition of histone acetylation (12,13,35). Highlighted in a recent review, these discrepancies may reflect long-term adaptations to an ACLY loss as well as off-target effects of the inhibitors (36).…”

Section: Discussionmentioning

confidence: 99%

Impact of ATP-citrate lyase catalytic activity and serine 455 phosphorylation on histone acetylation and inflammatory responses in human monocytic THP-1 cells

et al. 2022

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ATP-citrate lyase (ACLY) is a key enzyme provoking metabolic and epigenetic gene regulation. Molecularly, these functions are exerted by the provision of acetyl-coenzyme A, which is then used as a substrate for de novo lipogenesis or as an acetyl-group donor in acetylation reactions. It has been demonstrated that ACLY activity can be positively regulated via phosphorylation at serine 455 by Akt and protein kinase A. Nonetheless, the impact of phosphorylation on ACLY function in human myeloid cells is poorly understood. In this study we reconstituted ACLY knockout human monocytic THP-1 cells with a wild type ACLY as well as catalytically inactive H760A, and phosphorylation-deficient S455A mutants. Using these cell lines, we determined the impact of ACLY activity and phosphorylation on histone acetylation and pro-inflammatory gene expression in response to lipopolysaccharide (LPS). Our results show that ACLY serine 455 phosphorylation does not influence the proper enzymatic function of ACLY, since both, wild type ACLY and phosphorylation-deficient mutant, exhibited increased cell growth and histone acetylation as compared to cells with a loss of ACLY activity. Transcriptome analysis revealed enhanced expression of pro-inflammatory and interferon response genes in ACLY knockout and H760A THP-1 cells under unstimulated or LPS-treated conditions. At the same time, S455A ACLY-expressing cells showed a phenotype very similar to wild type cells. Contrary to ACLY knockout, pharmacological inhibition of ACLY in THP-1 cells or in primary human macrophages does not enhance LPS-triggered pro-inflammatory gene expression. Our data thus suggest that ACLY retains functionality in the absence of Akt/PKA-mediated phosphorylation in human myeloid cells. Furthermore, loss of ACLY activity may elicit long-term adaptive mechanisms, increasing inflammatory responses.

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“…Our results also indicate an increase in the export of citrate to the cytoplasm and the ratio succinate/α-KG, two important features of M1 macrophages(86). Once in the cytoplasm, citrate and succinate act as signaling molecules (94), thus activating proin ammatory transcription factors such as HIF-1α(7), ROS production (27), and epigenetic regulation linked to an M1 phenotype (95). In contrast, cytoplasmic α-KG is anti-in ammatory, being able to block NF-κB activation (9).…”

Section: Discussionmentioning

confidence: 99%

Immunometabolic actions of trabectedin and lurbinectedin on human macrophages: Relevance for their antitumor activity

Povo‐Retana¹,

Fariñas

Landauro-Vera³

et al. 2023

Preprint

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In recent years, the central role of cell bioenergetics in regulating immune cell function and fate has been recognized, giving rise to the interest in immunometabolism, an area of research focused on the interaction between metabolic regulation and immune function. Thus, early metabolic changes associated with the polarization of macrophages into pro-inflammatory or pro-resolving cells under different stimuli have been characterized. Tumor-associated macrophages are among the most abundant cells in the tumor microenvironment; however, it exists an unmet need to study the effect of chemotherapeutics on macrophage immunometabolism. Here, we use a systems biology approach that integrates transcriptomics and metabolomics to unveil the immunometabolic effects of trabectedin (TRB) and lurbinectedin (LUR), two DNA-binding agents with proven antitumor activity. Our results show that TRB and LUR activate human macrophages toward a pro-inflammatory phenotype by inducing a specific metabolic rewiring program that includes ROS production, changes in the mitochondrial inner membrane potential, increased pentose phosphate pathway, lactate release, TCA cycle, serine and methylglyoxal pathways in human macrophages. Glutamine, aspartate, histidine, and proline intracellular levels are also decreased, whereas oxygen consumption is reduced. The observed immunometabolic changes could explain additional antitumor activities of these compounds and open new avenues to design therapeutic interventions that specifically target the immunometabolic landscape in the treatment of cancer.

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Blockage of citrate export prevents TCA cycle fragmentation via Irg1 inactivation

Cited by 49 publications

References 56 publications

Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5

Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5

Impact of ATP-citrate lyase catalytic activity and serine 455 phosphorylation on histone acetylation and inflammatory responses in human monocytic THP-1 cells

Immunometabolic actions of trabectedin and lurbinectedin on human macrophages: Relevance for their antitumor activity

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