Give it or take it: the flux of one-carbon in cancer cells

The sequence of the human genome together with sequence similarity analyses has advanced the discovery of missing steps in the mitochondrial one‐carbon metabolism pathway. That together with the revived interest in cancer metabolism has brought the research on one‐carbon metabolism back under the spotlight. Here, we present a brief review of recent advances in the field of one‐carbon metabolism, with a bias towards its relevance to cell growth and proliferation in human cancers. We will address the requirements of one‐carbon metabolism for biosynthesis and the major sources to satisfy that demand. We will also discuss some recent discoveries indicating a role of one‐carbon metabolism beyond biosynthesis. We conclude with a concise enumeration of some fundamental questions that remain unanswered

DJ1 at the interface between neuro-degeneration and cancer

No abstract available

Iron dependent post-translational regulation of the bHLH transcription factor FIT in Arabidopsis thaliana

Iron (Fe) is an essential micronutrient for most organisms, but too high Fe contents can cause the formation of free radicals. Hence, Fe uptake must be tightly regulated. Root iron acquisition in non-graminaceous plants, like the model plant Arabidopsis thaliana, is achieved by reduction of soil Fe by the reductase FRO2 and its subsequent uptake by the metal transporter IRT1. The bHLH transcription factor FIT is required for high-level expression of FRO2 and IRT1 upon Fe deficiency. In this work we investigated post-transcriptional regulation of FIT. We found Fe dependent post-transcriptional regulation of FIT in way of constant turnover. Small amounts of active FIT were found to be sufficient to trigger the expression of FRO2 and IRT1. FIT protein stability relies on the presence of the signalling compound nitric oxide (NO). NO mediated stabilisation of FIT is independent of transcriptional regulation and is most probably achieved by counteracting proteasome dependent degradation of FIT. We summarise our results in an integrative model and based on this we made further efforts to identify post-translational modifications that could regulate FIT activity. Based on in silico prediction we identified four amino acids in the c-terminal part of FIT as putative phosphorylation sites. With newly generated FIT forms containing phosphomicking or non-phosphorylatable mutations we can draw further conclusions and suggest that phosphorylation may regulate FIT activity.Eisen (Fe) ist ein essentieller Mikronährstoff für Lebewesen. Jedoch können zu hohe Konzentrationen an Eisen die Bildung freier Radikale zur Folge haben. Die Eisenaufnahme aus dem Boden erfolgt bei der Modellpflanze Arabidopsis thaliana, sowie bei allen Nicht-Gräsern, mittels Reduzierung des im Boden enthaltenen Eisens, durch die Reduktase FRO2 und durch die Aufnahme des Metalltransporters IRT1. Bei Eisenmangel wird der bHLH Transkriptionsfaktor FIT für die verstärkte Transkription von FRO2 und IRT1 benötigt. In dieser Arbeit wurde die post-transkriptionelle Regulation von FIT untersucht und es konnte eine eisenabhängige Regulation von FIT nachgewiesen werden. Geringe Mengen an FIT waren ausreichend um die Expression der Zielgene zu induzieren. Die Stabilität von FIT ist abhängig von dem Signalmolekül Stickstoffmonoxid (NO). Die transkriptionsunabhängige Stabilisierung von FIT durch NO erfolgt wahrscheinlich durch eine Hemmung der Proteasom-abhängigen Degradation von FIT. Wir haben unsere Ergebnisse in einem Modell zusammengefasst und weisen darauf basierend post-translationale Mechanismen auf, welche die Aktivität von FIT regulieren könnten. Vier Aminosäuren innerhalb des c-terminalen Teils von FIT wurden anhand von in silico Analysen als mögliche Phosphorylierungsstellen identifiziert. Neu hergestellte FIT Formen, welche eine Phosphorylierung oder eine Dephosphorylierung imitieren, zeigten, dass Phosphorylierung ein potentieller Faktor ist, um die FIT-Aktivität zu regulieren

Formate metabolism in health and disease

Background: Formate is a one-carbon molecule at the crossroad between cellular and whole body metabolism, between host and microbiome metabolism, and between nutrition and toxicology. This centrality confers formate with a key role in human physiology and disease that is currently unappreciated. Scope of review: Here we review the scientific literature on formate metabolism, highlighting cellular pathways, whole body metabolism, and interactions with the diet and the gut microbiome. We will discuss the relevance of formate metabolism in the context of embryonic development, cancer, obesity, immunometabolism, and neurodegeneration. Major conclusions: We will conclude with an outlook of some open questions bringing formate metabolism into the spotlight

Washout and Awakening Times after Inhaled Sedation of Critically Ill Patients: Desflurane Versus Isoflurane

In recent years, inhaled sedation has been increasingly used in the intensive care unit (ICU). The aim of this prospective, controlled trial was to compare washout and awakening times after long term sedation with desflurane and isoflurane both administered with the MIRUS™ system (TIM GmbH, Koblenz, Germany). Twenty-one consecutive critically ill patients were alternately allocated to the two study groups, obtaining inhaled sedation with either desflurane or isoflurane. After 24 h study sedation, anesthetic washout curves were recorded, and a standardized wake-up test was performed. The primary outcome measure was the time required to decrease the endtidal concentration to 50% (T50%). Secondary outcome measures were T80% and awakening times (all extremities moved, RASS −2). Decrement times (min) (desflurane versus isoflurane, median (1st quartile—3rd quartile)) (T50%: 0.3 (0.3–0.4) vs. 1.3 (0.4–2.3), log-rank test P = 0.002; P80%: 2.5 (2–5.9) vs. 12.1 (5.1–20.2), P = 0.022) and awakening times (to RASS −2: 7.5 (5.5–8.8) vs. 41.0 (24.5–43.0), P = 0.007; all extremities moved: 5.0 (4.0–8.5) vs. 13.0 (8.0–41.25), P = 0.037) were significantly shorter after desflurane compared to isoflurane. The use of desflurane with the MIRUS™ system significantly shortens the washout times and leads to faster awakening after sedation of critically ill patients

Serine one-carbon catabolism with formate overflow

Serine catabolism to glycine and a one-carbon unit has been linked to the anabolic requirements of proliferating mammalian cells. However, genome-scale modeling predicts a catabolic role with one-carbon release as formate. We experimentally prove that in cultured cancer cells and nontransformed fibroblasts, most of the serine-derived one-carbon units are released from cells as formate, and that formate release is dependent on mitochondrial reverse 10-CHO-THF synthetase activity. We also show that in cancer cells, formate release is coupled to mitochondrial complex I activity, whereas in nontransformed fibroblasts, it is partially insensitive to inhibition of complex I activity. We demonstrate that in mice, about 50% of plasma formate is derived from serine and that serine starvation or complex I inhibition reduces formate synthesis in vivo. These observations transform our understanding of one-carbon metabolism and have implications for the treatment of diabetes and cancer with complex I inhibitors

Itaconic acid indicates cellular but not systemic immune system activation

Itaconic acid is produced by mammalian leukocytes upon pro-inflammatory activation. It appears to inhibit bacterial growth and to rewire the metabolism of the host cell by inhibiting succinate dehydrogenase. Yet, it is unknown whether itaconic acid acts only intracellularly, locally in a paracrine fashion, or whether it is even secreted from the inflammatory cells at meaningful levels in peripheral blood of patients with severe inflammation or sepsis. The aim of this study was to determine the release rate of itaconic acid from pro-inflammatory activated macrophages in vitro and to test for the abundance of itaconic acid in bodyfluids of patients suffering from acute inflammation. We demonstrate that excretion of itaconic acid happens at a low rate and that it cannot be detected in significant amounts in plasma or urine of septic patients or in liquid from bronchial lavage of patients with pulmonary inflammation. We conclude that itaconic acid may serve as a pro-inflammatory marker in immune cells but that it does not qualify as a biomarker in the tested body fluids

Formate induces a metabolic switch in nucleotide and energy metabolism

Formate is a precursor for the de novo synthesis of purine and deoxythymidine nucleotides. Formate also interacts with energy metabolism by promoting the synthesis of adenine nucleotides. Here we use theoretical modelling together with metabolomics analysis to investigate the link between formate, nucleotide and energy metabolism. We uncover that endogenous or exogenous formate induces a metabolic switch from low to high adenine nucleotide levels, increasing the rate of glycolysis and repressing the AMPK activity. Formate also induces an increase in the pyrimidine precursor orotate and the urea cycle intermediate argininosuccinate, in agreement with the ATP-dependent activities of carbamoyl-phosphate and argininosuccinate synthetase. In vivo data for mouse and human cancers confirms the association between increased formate production, nucleotide and energy metabolism. Finally, the in vitro observations are recapitulated in mice following and intraperitoneal injection of formate. We conclude that formate is a potent regulator of purine, pyrimidine and energy metabolism

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