Quantitative analysis of amino acid metabolism in liver cancer links glutamate excretion to nucleotide synthesis

Nilsson, Anders; Haanstra, Jurgen R.; Engqvist, Martin K. M.; Gerding, Albert; Bakker, Barbara M.; Klingmüller, Ursula; Teusink, Bas; Nielsen, Jens

doi:10.1073/pnas.1919250117

Cited by 49 publications

(49 citation statements)

References 74 publications

(86 reference statements)

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“…Only alanine and aspartate are seen to be consumed during lactate consumption, while glutamate levels remain constant. The switch to alanine uptake upon glucose or glutamine limitation has been previously reported [51, 53]. Alanine has been suggested to serve as a carbon source for the TCA cycle through transamination‐derived pyruvate when glucose is scarce [45, 54].…”

Section: Resultsmentioning

confidence: 99%

Regulation of pyruvate dehydrogenase complex related to lactate switch in CHO cells

Möller

Bhat

Guhl

et al. 2020

Engineering in Life Sciences

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The metabolism of Chinese hamster ovary (CHO) cell lines is typically characterized by high rates of aerobic glycolysis with increased lactate formation, known as the ”Warburg” effect. Although this metabolic state can switch to lactate consumption, the involved regulations of the central metabolism have only been partially studied so far. An important reaction transferring the lactate precursor, pyruvate, into the tricarboxylic acid cycle is the decarboxylation reaction catalyzed by the pyruvate dehydrogenase enzyme complex (PDC). Among other mechanisms, PDC is mainly regulated by phosphorylation–dephosphorylation at the three sites Ser232, Ser293, and Ser300. In this work, the PDC phosphorylation in antibody‐producing CHO DP‐12 cell culture is investigated during the lactate switch. Batch cultivations were carried out with frequent sampling (every 6 h) during the transition from lactate formation to lactate uptake, and the PDC phosphorylation levels were quantified using a novel indirect flow cytometry protocol. Contrary to the expected activation of PDC (i.e., reduced PDC phosphorylation) during lactate consumption, Ser293 and Ser300 phosphorylation levels were 33% higher compared to the phase of glucose excess. At the same time, the relative phosphorylation level of Ser232 increased steadily throughout the cultivation (66% increase overall). The intracellular pyruvate was found to accumulate only during the period of high lactate production, while acetyl‐CoA showed nearly no accumulation. These results indicate a deactivation of PDC and reduced oxidative metabolism during lactate switch even though the cells undergo a metabolic transition to lactate‐based cell growth and metabolism. Overall, this study provides a unique view on the regulation of PDC during the lactate switch, which contributes to an improved understanding of PDC and its interaction with the bioprocess.

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Section: Resultsmentioning

confidence: 99%

Regulation of pyruvate dehydrogenase complex related to lactate switch in CHO cells

Möller

Bhat

Guhl

et al. 2020

Engineering in Life Sciences

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“…Glutamine has long been considered an essential metabolite for tumor cell growth (Oizel et al, 2017;Nilsson et al, 2020;Still and Yuneva, 2017;Mckeehan, 1982;Dang, 2010). We described how glutamine-derived a-ketoglutarate could branch out to become a substrate for both the reductive carboxylation and the oxidative decarboxylation pathways in the TCA cycle (Chinopoulos and Seyfried, 2018).…”

Section: Glutamine-driven Mslp: An Unrecognized Mechanism For Atp Synmentioning

confidence: 99%

“…The calorie-restricted ketogenic diet (KD-R) will reduce glucose carbons for both the glycolytic pathway and the pentose phosphate pathway (PPP) that supply ATP and metabolic precursors for synthesis of glutathione, lipids, and nucleotides. Glutaminase inhibitors, like 6-diazo-5-oxo-L-norleucine (DON), will deplete glutamate and the glutamine-derived amide nitrogen needed for ammonia and nucleotide synthesis (Nilsson et al, 2020). Depletion of glutamine-derived glutamate will reduce anapleurotic carbons to the TCA cycle through a-KG for protein synthesis, while also reducing energy production through the succinyl-CoA ligase reaction in the TCA cycle.…”

Section: Limitationsmentioning

confidence: 99%

On the Origin of ATP Synthesis in Cancer

et al. 2020

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ATP is required for mammalian cells to remain viable and to perform genetically programmed functions. Maintenance of the DG 0 ATP hydrolysis of À56 kJ/mole is the endpoint of both genetic and metabolic processes required for life. Various anomalies in mitochondrial structure and function prevent maximal ATP synthesis through OxPhos in cancer cells. Little ATP synthesis would occur through glycolysis in cancer cells that express the dimeric form of pyruvate kinase M2. Mitochondrial substrate level phosphorylation (mSLP) in the glutamine-driven glutaminolysis pathway, substantiated by the succinate-CoA ligase reaction in the TCA cycle, can partially compensate for reduced ATP synthesis through both Ox-Phos and glycolysis. A protracted insufficiency of OxPhos coupled with elevated glycolysis and an auxiliary, fully operational mSLP, would cause a cell to enter its default state of unbridled proliferation with consequent dedifferentiation and apoptotic resistance, i.e., cancer. The simultaneous restriction of glucose and glutamine offers a therapeutic strategy for managing cancer.

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“…The modeling and simulations can examine not only the details of modular metabolic pathways of a mitochondrion, but can also be used to describe interactions of these pathways [ 117 , 118 ]. The major pathways ( Figure 5 ) include energy metabolism [ 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 ], ROS production [ 117 , 118 , 119 , 120 , 121 , 122 ], amino acid metabolism [ 123 ], calcium homeostasis [ 124 , 125 ], and biosynthesis of various molecules [ 126 ] ( Figure 5 ). Dysfunctions of these pathways are critical for the development of neurodegenerative diseases directly or indirectly via ROS-related pathways [ 19 , 127 ].…”

Section: Computational Modeling Of Mitochondria In Brain Disordersmentioning

confidence: 99%

Power Failure of Mitochondria and Oxidative Stress in Neurodegeneration and Its Computational Models

et al. 2021

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The brain needs more energy than other organs in the body. Mitochondria are the generator of vital power in the living organism. Not only do mitochondria sense signals from the outside of a cell, but they also orchestrate the cascade of subcellular events by supplying adenosine-5′-triphosphate (ATP), the biochemical energy. It is known that impaired mitochondrial function and oxidative stress contribute or lead to neuronal damage and degeneration of the brain. This mini-review focuses on addressing how mitochondrial dysfunction and oxidative stress are associated with the pathogenesis of neurodegenerative disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and Parkinson’s disease. In addition, we discuss state-of-the-art computational models of mitochondrial functions in relation to oxidative stress and neurodegeneration. Together, a better understanding of brain disease-specific mitochondrial dysfunction and oxidative stress can pave the way to developing antioxidant therapeutic strategies to ameliorate neuronal activity and prevent neurodegeneration.

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Quantitative analysis of amino acid metabolism in liver cancer links glutamate excretion to nucleotide synthesis

Cited by 49 publications

References 74 publications

Regulation of pyruvate dehydrogenase complex related to lactate switch in CHO cells

Regulation of pyruvate dehydrogenase complex related to lactate switch in CHO cells

On the Origin of ATP Synthesis in Cancer

Power Failure of Mitochondria and Oxidative Stress in Neurodegeneration and Its Computational Models

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