Glutamine reliance in cell metabolism

Yoo, Hee Chan; Yu, Ya Chun; Sung, Yulseung; Han, Jung Min

doi:10.1038/s12276-020-00504-8

Cited by 568 publications

(454 citation statements)

References 206 publications

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“…The few that were detected were present at relatively low levels compared with those present in other amino acid-degradative processes such as glutaminolysis. This may be related to the reduced accessibility of these alternatives in culture medium and their less preferential metabolic utilisation compared with glutamine [64]. Of those that were detected, the expression of two was significantly altered in ME/CFS lymphoblast proteomes.…”

Section: Expression Of Enzymes Involved In the Mitochondrial Utilisatmentioning

confidence: 99%

Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts

Missailidis

Sanislav

Allan

et al. 2021

IJMS

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Although understanding of the biomedical basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is growing, the underlying pathological mechanisms remain uncertain. We recently reported a reduction in the proportion of basal oxygen consumption due to ATP synthesis by Complex V in ME/CFS patient-derived lymphoblast cell lines, suggesting mitochondrial respiratory inefficiency. This was accompanied by elevated respiratory capacity, elevated mammalian target of rapamycin complex 1 (mTORC1) signaling activity and elevated expression of enzymes involved in the TCA cycle, fatty acid β-oxidation and mitochondrial transport. These and other observations led us to hypothesise the dysregulation of pathways providing the mitochondria with oxidisable substrates. In our current study, we aimed to revisit this hypothesis by applying a combination of whole-cell transcriptomics, proteomics and energy stress signaling activity measures using subsets of up to 34 ME/CFS and 31 healthy control lymphoblast cell lines from our growing library. While levels of glycolytic enzymes were unchanged in accordance with our previous observations of unaltered glycolytic rates, the whole-cell proteomes of ME/CFS lymphoblasts contained elevated levels of enzymes involved in the TCA cycle (p = 1.03 × 10−4), the pentose phosphate pathway (p = 0.034, G6PD p = 5.5 × 10−4), mitochondrial fatty acid β-oxidation (p = 9.2 × 10−3), and degradation of amino acids including glutamine/glutamate (GLS p = 0.034, GLUD1 p = 0.048, GOT2 p = 0.026), branched-chain amino acids (BCKDHA p = 0.028, BCKDHB p = 0.031) and essential amino acids (FAH p = 0.036, GCDH p = 0.006). The activity of the major cellular energy stress sensor, AMPK, was elevated but the increase did not reach statistical significance. The results suggest that ME/CFS metabolism is dysregulated such that alternatives to glycolysis are more heavily utilised than in controls to provide the mitochondria with oxidisable substrates.

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Section: Expression Of Enzymes Involved In the Mitochondrial Utilisatmentioning

confidence: 99%

Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts

Missailidis

Sanislav

Allan

et al. 2021

IJMS

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“…In the current research, we verified that miR-330-3p directly bound to GLS 3'-UTR and negatively regulated GLS expression. Aberrant energy metabolism, such as increased glutamine catabolism, is one of critical hallmarks of cancer (33,34). In addition to abnormal glycolysis, several previous studies revealed that enhanced glutamine metabolism was correlated with tumor metastasis and poor prognosis in patients with cancer (12,35).…”

Section: Discussionmentioning

confidence: 99%

Circ_0000003 regulates glutamine metabolism and tumor progression of tongue squamous cell carcinoma via the miR‑330‑3p/GLS axis

Qian

Chen

et al. 2021

Oncol Rep

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Various circular RNAs (circRNAs) have been shown to exert vital functions in tongue squamous cell carcinoma (TSCC). However, their roles in TSCC progression remain to be elucidated. This research aimed to investigate the role and mechanism of hsa_circ_0000003 (circ_0000003) in TSCC progression. Here, we found that circ_0000003 expression was upregulated in TSCC tissues and cell lines, and high circ_0000003 expression was correlated with advanced TNM stage, increased tumor size and poor patient survival. Circ_0000003 was revealed to facilitate cell proliferation, migration and invasion of TSCC cells. Mechanistically, we found that circ_0000003 acted as a competing endogenous RNA (ceRNA) that sponged miR-330-3p, thereby elevating glutaminase (GLS) expression. Accordingly, cell invasion, migration, glutamine consumption, α-ketoglutarate (α-KG) production and ATP production were significantly decreased by circ_0000003 knockdown in TSCC cells, and these effects were reversed by miR-330-3p inhibition. In conclusion, circ_0000003 facilitates TSCC cell proliferation, migration, invasion and glutamine catabolism by regulating the miR-330-3p/GLS pathway.

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“…Glutamine is both a cellular building block and an indirect fuel for the TCA cycle 38, 39 and was described as the primary energy fuel for HeLa cells 40 . Depending on the cellular metabolic state, glutamine can be used as either a biosynthetic precursor for proteins, nucleotides or glutathione, or as an anaplerotic fuel that drives mitochondrial ATP production 41, 42 . Without its presence in glucose-free culture medium, it is difficult to predict the adaptations in energy metabolism of NHDF cells.…”

Section: Discussionmentioning

confidence: 99%

“…Pyruvate can be converted into acetyl-CoA and enter the TCA cycle, thus being an energy source for cells 46 . However, if pyruvate is the only source of energy, this will probably only work in short-term because there would be no source to maintain the pool of TCA cycle intermediates that are used in other metabolic pathways, as opposed to what happens when glutamine is the main fuel 41 . Pyruvate supplementation in culture media without glucose is not entirely consensual.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial and metabolic remodeling in human skin fibroblasts in response to glucose availability

Costa

Pinho

Santos

et al. 2021

Preprint

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Cell culture conditions highly influence cell metabolism in vitro. This is relevant for preclinical assays, for which fibroblasts are an interesting cell model, with applications in regenerative medicine, diagnostics and therapeutic development for personalized medicine as well as in the validation of ingredients for cosmetics. Given these cells short lifespan in culture, we aimed to identify the best cell culture conditions and promising markers to study mitochondrial health and stress in Normal Human Dermal Fibroblasts (NHDF). We tested the effect of reducing glucose concentration in the cell medium from high glucose (HGm) to a more physiological level (LGm), or its complete removal and replacement by galactose (OXPHOSm), always in the presence of glutamine and pyruvate. We have demonstrated that only with OXPHOSm it was possible to observe the selective inhibition of mitochondrial ATP production. This reliance on mitochondrial ATP was accompanied by changes in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), oxidation of citric acid cycle substrates, fatty acids, lactate and other substrates, mitochondrial network extension and polarization and changes in several key transcripts related to energy metabolism. We also evaluated the relevance of galactose, glutamine and pyruvate for OXPHOS stimulation, by comparing OCR and ECAR in the presence or absence of these substrates. Galactose and pyruvate seem to be important, but redundant, to promote OXPHOS, whereas glutamine was essential. We concluded that LGm does not promote significant metabolic changes but the short-term adaptation to OXPHOSm is ideal for studying mitochondrial health and stress in NHDF.

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Glutamine reliance in cell metabolism

Cited by 568 publications

References 206 publications

Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts

Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts

Circ_0000003 regulates glutamine metabolism and tumor progression of tongue squamous cell carcinoma via the miR‑330‑3p/GLS axis

Mitochondrial and metabolic remodeling in human skin fibroblasts in response to glucose availability

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