NaCT/SLC13A5 facilitates citrate import and metabolism under nutrient-limited conditions

Kumar, Avi; Cordes, Thekla; Thalacker‐Mercer, Anna; Pajor, Ana M.; Murphy, Anne N.; Metallo, Christian M.

doi:10.1016/j.celrep.2021.109701

Cited by 24 publications

(19 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, another recent report that used a different mINDY-KO mouse model described increased motor coordination and improved recognition and social memory, which were similar to CR mice [ 53 ]. The role of mINDY in metabolism is further underscored by studies that show that silencing mINDY in human hepatocarcinoma cells decreases their proliferation [ 54 , 55 , 56 ].…”

Section: The Role Of Indy In Metabolismmentioning

confidence: 99%

The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis

Kannan

Rogina

2021

Metabolites

View full text Add to dashboard Cite

I’m Not Dead Yet (Indy) is a fly gene that encodes a homologue of mammalian SLC13A5 plasma membrane citrate transporter. Reducing expression of Indy gene in flies, and its homologues in worms, extends longevity. Indy reduction in flies, worms, mice and rats affects metabolism by regulating the levels of cytoplasmic citrate, inducing a state similar to calorie restriction. Changes include lower lipid levels, increased insulin sensitivity, increased mitochondrial biogenesis, and prevention of weight gain, among others. The INDY protein is predominantly expressed in fly metabolic tissues: the midgut, fat body and oenocytes. Changes in fly midgut metabolism associated with reduced Indy gene activity lead to preserved mitochondrial function and reduced production of reactive oxygen species. All these changes lead to preserved intestinal stem cell homeostasis, which has a key role in maintaining intestinal epithelium function and enhancing fly healthspan and lifespan. Indy gene expression levels change in response to caloric content of the diet, inflammation and aging, suggesting that INDY regulates metabolic adaptation to nutrition or energetic requirements by controlling citrate levels.

show abstract

Section: The Role Of Indy In Metabolismmentioning

confidence: 99%

The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis

Kannan

Rogina

2021

Metabolites

View full text Add to dashboard Cite

show abstract

“…As for energy metabolism, serum citrate levels were also elevated after treatment and positively correlated with total protein levels. Citrate is synthesized by citrate synthase and is an intermediate in the interconversion of various substances in the body[ 22 ]. It serves as a consuming substrate for the tricarboxylic acid (TCA) cycle, increasing production of ATP via the TCA cycle with oxidative phosphorylation pathways in ARDS.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics profile in acute respiratory distress syndrome by nuclear magnetic resonance spectroscopy in patients with community-acquired pneumonia

et al. 2022

View full text Add to dashboard Cite

BackgroundAcute respiratory distress syndrome (ARDS) is a challenging clinical problem. Discovering the potential metabolic alterations underlying the ARDS is important to identify novel therapeutic target and improve the prognosis. Serum and urine metabolites can reflect systemic and local changes and could help understanding metabolic characterization of community-acquired pneumonia (CAP) with ARDS.MethodsClinical data of patients with suspected CAP at the First Affiliated Hospital of Wenzhou Medical University were collected from May 2020 to February 2021. Consecutive patients with CAP were enrolled and divided into two groups: CAP with and without ARDS groups.1H nuclear magnetic resonance-based metabolomics analyses of serum and urine samples were performed before and after treatment in CAP with ARDS (n = 43) and CAP without ARDS (n = 45) groups. Differences metabolites were identifed in CAP with ARDS. Furthermore, the receiver operating characteristic (ROC) curve was utilized to identify panels of significant metabolites for evaluating therapeutic effects on CAP with ARDS. The correlation heatmap was analyzed to further display the relationship between metabolites and clinical characteristics.ResultsA total of 20 and 42 metabolites were identified in the serum and urine samples, respectively. Serum metabolic changes were mainly involved in energy, lipid, and amino acid metabolisms, while urine metabolic changes were mainly involved in energy metabolism. Elevated levels of serum 3-hydroxybutyrate, lactate, acetone, acetoacetate, and decreased levels of serum leucine, choline, and urine creatine and creatinine were detected in CAP with ARDS relative to CAP without ARDS. Serum metabolites 3-hydroxybutyrate, acetone, acetoacetate, citrate, choline and urine metabolite 1-methylnicotinamide were identified as a potential biomarkers for assessing therapeutic effects on CAP with ARDS, and with AUCs of 0.866 and 0.795, respectively. Moreover, the ROC curve analysis revealed that combined characteristic serum and urine metabolites exhibited a better classification system for assessing therapeutic effects on CAP with ARDS, with a AUC value of 0.952. In addition, differential metabolites strongly correlated with clinical parameters in patients with CAP with ARDS.ConclusionsSerum- and urine-based metabolomics analyses identified characteristic metabolic alterations in CAP with ARDS and might provide promising circulatory markers for evaluating therapeutic effects on CAP with ARDS.

show abstract

“…This could result in reduced activity of the non-oxidative PPP. Therefore, uptake of extracellular citrate might play a regulatory role in activating the oxidative PPP through (1) increased NADP + levels resulting from increased fatty acid synthesis [ 1 , 47 ], (2) as well as through inhibition of PFK-1. In this case, citrate taken up from the extracellular space could play a role not only in inducing OXPHOS and supporting fatty acid synthesis but also regulating metabolic pathways leading to a better protection of cancer cells against ROS.…”

Section: Citrate In Redox Balancementioning

confidence: 99%

Extracellular citrate and metabolic adaptations of cancer cells

Parkinson

Adamski

Zahn³

et al. 2021

Cancer Metastasis Rev

View full text Add to dashboard Cite

It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity.

show abstract

NaCT/SLC13A5 facilitates citrate import and metabolism under nutrient-limited conditions

Abstract: Highlights d HCC cells utilize NaCT-mediated citrate uptake for lipogenesis d Citrate import supports lipogenesis and anaplerosis upon glutamine deprivation d NaCT-mediated citrate uptake facilitates protection against zinc toxicity

Cited by 24 publications

References 67 publications

The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis

The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis

Metabolomics profile in acute respiratory distress syndrome by nuclear magnetic resonance spectroscopy in patients with community-acquired pneumonia

Extracellular citrate and metabolic adaptations of cancer cells

Contact Info

Product

Resources

About