Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer

Villar, Victor H.; Allega, Maria Francesca; Deshmukh, Ruhi; Ackermann, Tobias; Nakasone, Mark A.; Voorde, Johan Vande; Drake, Thomas M; Oetjen, Janina; Bloom, Algernon; Nixon, Colin; Müller, Miryam; May, Stephanie; Tan, Ee Hong; Vereecke, Lars; Jans, Maude; Blancke, Gillian; Murphy, Daniel J.; Huang, Danny T.; Lewis, David Y.; Bird, Tom; Sansom, Owen J.; Blyth, Karen; Sumpton, David; Tardito, Saverio

doi:10.1038/s41589-022-01154-9

Cited by 12 publications

(16 citation statements)

References 42 publications

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“…Thus, long-term NMP, as performed here, will be needed to reduce TG content to levels that would enable resistance to ischemia-reperfusion injury and amelioration in metabolic function, both prerequisites for successful transplantation 38,39 . Although there is room for improvement, metabolic zonation was maintained much longer with circadian feeding, providing additional evidence for the preservation of metabolic capacity during long-term NMP 40,41 …”

Section: Discussionmentioning

confidence: 84%

Defatting of Human Livers during Long-Term ex situ Normothermic Perfusion. Novel Strategy to Rescue Discarded Organs for Transplantation

et al. 2023

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Objective: To develop a protocol for the defatting of steatotic liver grafts during long-term ex situ normothermic machine perfusion. Background: Despite the alarming increase in donor organ shortage, the highly prevalent fatty liver grafts are often discarded due to the risk of primary non-function. Effective strategies preventing such outcome are currently lacking. An exciting new avenue is the introduction of ex situ normothermic machine perfusion (NMP), enabling a liver to remain fully functional for up to two weeks and providing a unique window of opportunity for defatting prior to transplantation. Methods: Over a 5-year period, 23 discarded liver grafts and 28 partial livers from our resection program were tested during ex situ NMP. The steatosis degree was determined on serial biopsies by expert pathologists, and triglyceride contents measured simultaneously. Results: Of 51 liver grafts, 20 were steatotic, with up to 85% macrovesicular steatosis, and were perfused for up to 12 days. 10 livers displayed marked (5 of which almost complete) loss of fat, while the other 10 did not respond to long-term perfusion. Successful defatting was related to prolonged perfusion, automated glucose control, circadian nutrition, and L-carnitine/fenofibrate supplementation. Pseudopeliotic steatosis and the associated activation of Kupffer/stellate cells were unexpected processes that might contribute to defatting. Synthetic and metabolic function remained preserved for most grafts until perfusion end. Conclusion: Ex situ long-term perfusion effectively reduces steatosis while preserving organ viability and may in the future allow transplantation of primarily unusable high-risk grafts, significantly increasing the number of organs available for transplantation.

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Section: Discussionmentioning

confidence: 84%

Defatting of Human Livers during Long-Term ex situ Normothermic Perfusion. Novel Strategy to Rescue Discarded Organs for Transplantation

et al. 2023

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“…; https://doi.org/10.1101/2023.03. 21.533091 doi: bioRxiv preprint cancer 1 , however the majority of variants observed somatically have not been detected in human disease or studied in the germline, thus requiring further study 1,7 . Hotspot truncating mutations in mitochondrial complex I genes are a common feature of several cancers, with truncating mutations in complex I (MT-ND5 in particular) being over-represented compared with mutations in genes encoding respiratory complexes III, IV and V 1 .…”

Section: Mainmentioning

confidence: 99%

“…; https://doi.org/10.1101/2023.03. 21.533091 doi: bioRxiv preprint consumption (Figure 1I), adenylate energy charge state (Figure 1J) or cell proliferation (Figure 1K). However, a ~10mV decrease in the electrical component of the mitochondrial proton motive force , Δ Ψ , coupled to a commensurate trend towards ~10mV increases in the chemical component , ΔpH, resulting in an unchanged total protonmotive force, ΔP, was detected (Extended Data Figure 3B).…”

Section: Mainmentioning

confidence: 99%

“…Mass spectrometry and subsequent targeted metabolomics analysis was performed as described in 21 . Compound peak areas were normalised using the total measured protein per well quantified with a modified Lzowry assay 21 .…”

Section: In Vitro Metabolomicsmentioning

confidence: 99%

“…Samples were run and subsequent targeted metabolomics analysis was performed as described in 21 . Compound peak areas were normalised using the mass of the tissue.…”

Section: Bulk Tumour Metabolomicsmentioning

confidence: 99%

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Tumour mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade

Mahmood

Liu

Shergold

et al. 2023

Preprint

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The mitochondrial genome encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutation in the cancer genome, with truncating mutations in respiratory complex I genes being most over-represented. While mitochondrial DNA (mtDNA) mutations have been associated with both improved and worsened prognoses in several tumour lineages, whether these mutations are drivers or exert any functional effect on tumour biology remains controversial. Here we discovered that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology, we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux without major effects on oxygen consumption, driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment in both mice and humans, promoting an anti-tumour immune response characterised by loss of resident neutrophils. This subsequently sensitised tumours bearing high mtDNA mutant heteroplasmy to immune checkpoint blockade, with phenocopy of key metabolic changes being sufficient to mediate this effect. Strikingly, patient lesions bearing >50% mtDNA mutation heteroplasmy also demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.

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Ligand‐Independent Activation of Aryl Hydrocarbon Receptor and Attenuation of Glutamine Levels by Natural Deep Eutectic Solvent

Denis,

Toledo,

Hakim

et al. 2023

ChemBioChem

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Natural deep eutectic solvents (NADESs) are emerging sustainable alternatives to conventional organic solvents. Beyond their role as laboratory solvents, NADESs are increasingly explored in drug delivery and as therapeutics. Their increasing applications notwithstanding, our understanding of how they interact with biomolecules at multiple levels – metabolome, proteome, and transcriptome – within human cell remain poor. Here, we deploy integrated metabolomics, proteomics, and transcriptomics to probe how NADESs perturb the molecular landscape of human cells. In a human cell line model, we found that an archetypal NADES derived from choline and geranic acid (CAGE) significantly altered the metabolome, proteome, and transcriptome. CAGE upregulated indole‐3‐lactic acid and 4‐hydroxyphenyllactic acid levels, resulting in ligand‐independent activation of aryl hydrocarbon receptor to signal the transcription of genes with implications for inflammation, immunomodulation, cell development, and chemical detoxification. Further, treating the cell line with CAGE downregulated glutamine biosynthesis, a nutrient rapidly proliferating cancer cells require. The ability of CAGE to attenuate glutamine levels is potentially relevant for cancer treatment. These findings suggest that NADESs, even when derived from natural components like choline, can indirectly modulate cell biology at multiple levels, expanding their applications beyond chemistry to biomedicine and biotechnology.

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Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer

Cited by 12 publications

References 42 publications

Defatting of Human Livers during Long-Term ex situ Normothermic Perfusion. Novel Strategy to Rescue Discarded Organs for Transplantation

Defatting of Human Livers during Long-Term ex situ Normothermic Perfusion. Novel Strategy to Rescue Discarded Organs for Transplantation

Tumour mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade

Ligand‐Independent Activation of Aryl Hydrocarbon Receptor and Attenuation of Glutamine Levels by Natural Deep Eutectic Solvent

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