A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells

Yoo, Hee Chan; Park, Seung Joon; Nam, Miso; Kang, Juwon; Kim, Ki-Bum; Yeo, Joo Hye; Kim, Joon Ki; Heo, Yunkyung; Lee, Jun Young; Lee, Myeong Youl; Lee, Chang Woo; Kang, Jong Soon; Kim, Yun Hee; Lee, Jinu; Choi, Jong Myung; Hwang, Gwi Seo; Bang, Seungmin; Han, Jung Min

doi:10.1016/j.cmet.2019.11.020

Cited by 254 publications

(226 citation statements)

References 53 publications

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“…Glutamine levels decrease in severe and mild COVID-19 patients and this change negatively correlated with lactate dehydrogenase (LDH), C reactive protein (CRP), and PO2 levels, and positively with PCO2; these markers have been associated with lung damage and altered oxygen homeostasis in COVID-19 patients 16,17 . In vitro experiments also have demonstrated that hypoxia increases glutamine transport into the cells through HIF2-alpha upregulation of SLC1A5 genes 18 . These interconnected processes might potentially link glutamine hypoxic catabolism with NAD recycling and malate synthesis.…”

Section: Discussionmentioning

confidence: 99%

COVID-19 Metabolomic Profile: A Link Between Lung Dysfunction Markers and Altered Amino Acid Metabolism

Páez-Franco¹,

Torres-Ruíz²,

Sosa-Hernández³

et al. 2020

Preprint

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We identified the main changes in serum metabolites associated with severe (n=46) and mild (n=19) COVID-19 patients by gas chromatography coupled to mass spectrometry. The modified metabolic profiles were associated to an altered amino acid catabolism in hypoxic conditions. Noteworthy, three 𝛼-hydroxyl acids of amino acid origin increased with disease severity and correlated with altered oxygen saturation levels and clinical markers of lung damage. We hypothesize that the enzymatic conversion of 𝛼-keto-acids to 𝛼- hydroxyl-acids helps to maintain NAD recycling in patients with altered oxygen levels, highlighting the potential relevance of amino acid supplementation during SARS-CoV-2 infection.

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Section: Discussionmentioning

confidence: 99%

COVID-19 Metabolomic Profile: A Link Between Lung Dysfunction Markers and Altered Amino Acid Metabolism

Páez-Franco¹,

Torres-Ruíz²,

Sosa-Hernández³

et al. 2020

Preprint

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“…Many studies have shown that the plasma membrane carrier SLC1A5 is overexpressed in several tumors under the control of the c-Myc transcription factor, thus highlighting the important role played by this transporter in enhancing glutamine utilization in order to support cancers’ high proliferative rates [ 98 , 99 , 100 , 101 , 102 ]. Furthermore, a very recent study showed that a SLC1A5 carrier variant expressed under hypoxic conditions localizes to mitochondria and regulates the entry of glutamine, thus stimulating glutaminolysis and playing a key role in tumor metabolic reprogramming [ 103 ]. Further studies showed that the loss of function of the SLC1A5 carrier results in cell growth inhibition, autophagy, and apoptosis triggering in solid and hematopoietic malignancies [ 104 , 105 ].…”

Section: Targeting Mitochondrial Metabolism In Cancermentioning

confidence: 99%

Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment

Frattaruolo

Brindisi

Curcio

et al. 2020

IJMS

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Metabolic reprogramming is a hallmark of cancer, which implements a profound metabolic rewiring in order to support a high proliferation rate and to ensure cell survival in its complex microenvironment. Although initial studies considered glycolysis as a crucial metabolic pathway in tumor metabolism reprogramming (i.e., the Warburg effect), recently, the critical role of mitochondria in oncogenesis, tumor progression, and neoplastic dissemination has emerged. In this report, we examined the main mitochondrial metabolic pathways that are altered in cancer, which play key roles in the different stages of tumor progression. Furthermore, we reviewed the function of important molecules inhibiting the main mitochondrial metabolic processes, which have been proven to be promising anticancer candidates in recent years. In particular, inhibitors of oxidative phosphorylation (OXPHOS), heme flux, the tricarboxylic acid cycle (TCA), glutaminolysis, mitochondrial dynamics, and biogenesis are discussed. The examined mitochondrial metabolic network inhibitors have produced interesting results in both preclinical and clinical studies, advancing cancer research and emphasizing that mitochondrial targeting may represent an effective anticancer strategy.

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“…Targeting mitochondrial protein synthesis, electron transfer chain activities, or fatty acid oxidation (FAO) induced an energetic shift towards low OxPHOS and markedly enhanced anti-leukemic effects of AraC, suggesting a promising avenue to design new therapeutic strategies to fight AraC resistance in AML [8][9][10][11] . Mitochondrial energy metabolism and redox homeostasis also play crucial roles in response to chemotherapy in other types of hematological malignancies 12,13 and solid tumors [14][15][16][17][18][19][20] .…”

Section: Mainmentioning

confidence: 99%

“…Growing evidence shows that energy metabolism and mitochondrial adaptation impact the development and progression of cancer. Notably, several studies have shown that mitochondrial function and OxPHOS are associated with drug resistance8,[12][13][14]16,[18][19][20] .However, the mechanism by which AraC increases OxPHOS in AML cells has remained largely unknown. Our work demonstrates a major role of BCL2 in the metabolic control of cell death and apoptosis, especially in the context of AraC therapy.…”

mentioning

confidence: 99%

Mitochondrial determinants of response and resistance to venetoclax plus cytarabine duplet therapy in acute myeloid leukemia

Bosc

Gadaud

Bousard

et al. 2020

Preprint

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The development of resistance to conventional and targeted therapy represents a major clinical barrier in treatment of acute myeloid leukemia (AML). We show that the resistance to cytarabine (AraC) and its associated mitochondrial phenotype were reversed by genetic silencing or pharmacological inhibition of BCL2 in a caspase-dependent manner. BCL2-inhibitor venetoclax (VEN) enhancement of AraC efficacy was independent of differentiation phenotype, a characteristic of response to another combination of VEN with hypomethylating agents (HMA). Furthermore, transcriptional profiles of patients with low response to VEN+AraC mirrored those of low responders to VEN+HMA in clinical trials. OxPHOS was found to be a patient stratification marker predictive of effective response to VEN+AraC but not to VEN+AZA. Importantly, whereas three cell subpopulations specifically emerged in VEN+AraC residual disease and were characterized by distinct developmental and transcriptional programs largely driven by MITF, E2F4 and p53 regulons, they each encoded proteins involved in assembly of NADH dehydrogenase complex. Notably, treatment of VEN+AraC-persisting AML cells with an ETCI inhibitor significantly increased the time-to-relapse in vivo. These findings provide the scientific rationale for new clinical trials of VEN+AraC combinations, especially in patients relapsing or non-responsive to chemotherapy, or after failure of frontline VEN+HMA regimen

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A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells

Abstract: Highlights d The SLC1A5 variant is a mitochondrial glutamine transporter d The SLC1A5 variant has a mitochondrial targeting sequence d Hypoxia controls SLC1A5 variant expression through HIF-2a d The SLC1A5 variant mediates mitochondrial glutamine metabolism in cancer

Cited by 254 publications

References 53 publications

COVID-19 Metabolomic Profile: A Link Between Lung Dysfunction Markers and Altered Amino Acid Metabolism

COVID-19 Metabolomic Profile: A Link Between Lung Dysfunction Markers and Altered Amino Acid Metabolism

Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment

Mitochondrial determinants of response and resistance to venetoclax plus cytarabine duplet therapy in acute myeloid leukemia

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