Metabolic reconfiguration precedes transcriptional regulation in the antioxidant response

Ralser, Markus; Wamelink, Mirjam M. C.; Latkolik, Simone; Jansen, Erwin E.W.; Lehrach, Hans; Jakobs, Cornelis

doi:10.1038/nbt0709-604

Cited by 125 publications

(130 citation statements)

References 9 publications

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“…This definition can be extended, as more recent studies show that the metabolic flux is often controlled purely on a posttranslational basis [20,24]. The balance of metabolite concentrations requires their constant monitoring by cellular regulatory components.…”

Section: Glossarymentioning

confidence: 99%

“…Initially, GAPDH acts as a metabolic switch upon inactivation and reroutes the metabolic flux by blocking glycolysis, whereas glucose transporters and the PPP remain active [68,69]. This process is very fast; GAPDH is inactivated within seconds and PPP metabolites increase almost immediately [24]. A few minutes later, a genetic response is induced, by which the PPP is upregulated and glycolytic enzymes are downregulated [70].…”

Section: Metabolic Transitions Mediate Cellular Adaptationmentioning

confidence: 99%

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Regulatory crosstalk of the metabolic network

Grüning

Lehrach

Ralser

2010

Trends in Biochemical Sciences

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The metabolic network has a modular architecture, is robust to perturbations, and responds to biological stimuli and environmental conditions. Through monitoring by metabolite responsive macromolecules, metabolic pathways interact with the transcriptome and proteome. Whereas pathway interconnecting cofactors and substrates report on the overall state of the network, specialised intermediates measure the activity of individual functional units. Transitions in the network affect many of these regulatory metabolites, facilitating the parallel regulation of the timing and control of diverse biological processes. The metabolic network controls its own balance, chromatin structure and the biosynthesis of molecular cofactors; moreover, metabolic shifts are crucial in the response to oxidative stress and play a regulatory role in cancer.Evolution of the metabolic network and its structure Life probably began with the formation of compartmentalised autocatalytic chemical cycles. With the appearance of complex catalysts (ribonucleic acid-or protein-based enzymes), these cycles gained complexity, and evolved in their effectiveness and robustness [1]. These metabolic pathways now form the basis for life.As was the case for the first primitive life forms, the survival of today's complex organisms depends on the robustness and functionality of the metabolic framework [2]. To prevent and counteract perturbations in the flux, many biological control and sensor systems have evolved around the metabolic network. Metabolic pathways provide the cell with energy and supply macromolecular synthesis pathways with their required intermediates. They also balance metabolic systems under a variety of physiological conditions, and act as transducers and sensor systems for environmental conditions and stimuli. In addition, metabolic pathways are essential for crosstalk between metabolic regulatory components and the cellular transcriptome and proteome.As early as the 1960s, the principle that cells alter their gene expression in response to metabolic requirements has been known. The seminal work of Jacob and Monod, investigating the lac operon, uncovered one of the first examples of chemical-genetic regulation, by which bacterial cells adjust their enzyme production to the nutrient supply [3]. However, only recently have the broader implications of this principle emerged. Indeed, changes in the metabolic network not only control the metabolome, but they also have wide-ranging regulatory functions throughout biology.Most of the biochemical mechanisms that link the metabolic network to the transcriptome and proteome are incompletely understood. However, one type of regulation appears to be common: representative network intermediates bind to and modulate sensor function and activity of transcription factors, translational regulators, chromatin, enzymes, RNA molecules, and ion channels. Significant transcriptional changes around these intermediates identified them as reporter metabolites [4,5]. The use of intermediates as activity reporters ne...

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Section: Glossarymentioning

confidence: 99%

Section: Metabolic Transitions Mediate Cellular Adaptationmentioning

confidence: 99%

Regulatory crosstalk of the metabolic network

Grüning

Lehrach

Ralser

2010

Trends in Biochemical Sciences

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“…The aforementioned mechanisms of ROS detoxification work in tandem to enable cells to thrive even in toxic oxygenated environments. In recent times the role of metabolism and metabolic shifts in combatting oxidative stress has been greatly studied and elucidated (Mailloux et al, 2006;Ralser et al, 2009). By modulating the catabolic and anabolic pathways, organisms are able to produce key metabolites in the fight against ROS as well as limit the production of pro-oxidants by the TCA cycle.…”

Section: Detoxification Mechanismsmentioning

confidence: 99%

The role of formate in combatting oxidative stress

Thomas

Alhasawi

Auger

et al. 2015

Antonie van Leeuwenhoek

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As all aerobic organisms are exposed to oxidative stress, they are known to devise intricate mechanisms to counter reactive oxygen species (ROS). Metabolic networks contributing to the production of ketoacids are prominent in alleviating the oxidative burden. When glyoxylate detoxifies ROS, formate is the principal by-product generated.In this study the contribution of formate in enabling the survival of the microbe Pseudomonas fluorescens challenged by hydrogen peroxide (H2O2) has been elucidated.When grown in the presence of H2O2 (stressed culture), the levels of formate were higher in the spent fluid and the soluble cell-free extracts compared to the controls. Formate was subsequently utilized as a reducing factor to produce NADPH and succinate. The former is mediated by formate dehydrogenase (FDH-NADP), whose activity was enhanced in the stressed cells. Fumarate reductase (FRD) that catalyzes the conversion of fumarate into succinate was also markedly increased in the stressed cells. Metabolic adaptation is a pivotal tool in combatting oxidative stress. Formate, a by-product of glyoxylate-mediated detoxification of ROS is recuperated as a potent reductive fuel. It is becoming quite evident that this simple metabolite has other biological roles that have not been fully appreciated.

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“…Intermediates of glycolysis and the pentose phosphate pathway (PPP) were quantified by liquid chromatography tandem mass spectrometry LC-MS/MS as described earlier [29]. In brief, metabolites were extracted in Hanks' balanced salt solution containing 2% perchloric acid and spiked with an isotope-labeled internal standard ( 13 C 6 -glucose-6P).…”

Section: Liquid Chromatography Tandem Mass Spectrometrymentioning

confidence: 99%

Human Induced Pluripotent Stem Cells Harbor Homoplasmic and Heteroplasmic Mitochondrial DNA Mutations While Maintaining Human Embryonic Stem Cell–like Metabolic Reprogramming

et al. 2011

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Human induced pluripotent stem cells (iPSCs) have been recently found to harbor genomic alterations. However, the integrity of mitochondrial DNA (mtDNA) within reprogrammed cells has yet to be investigated. mtDNA mutations occur at a high rate and contribute to the pathology of a number of human disorders. Furthermore, the lack of mtDNA integrity may alter cellular bioenergetics and limit efficient differentiation. We demonstrated previously that the derivation of iPSCs is associated with mitochondrial remodeling and a metabolic switch towards glycolysis. Here, we have discovered that alterations of mtDNA can occur upon the induction of pluripotency. Massively parallel pyrosequencing of mtDNA revealed that human iPSCs derived from young healthy donors harbored single base mtDNA mutations (substitutions, insertions, and deletions), both homoplasmic (in all mtDNA molecules) and heteroplasmic (in a fraction of mtDNAs), not present in the parental cells. mtDNA modifications were mostly common variants and not disease related. Moreover, iPSC lines bearing different mtDNA mutational loads maintained a consistent human embryonic stem cell-like reprogramming of energy metabolism. This involved the upregulation of glycolytic enzymes, increased glucose-6-phosphate levels, and the over-expression of pyruvate dehydrogenase kinase 1 protein, which reroutes the bioenergetic flux toward glycolysis. Hence, mtDNA mutations within iPSCs may not necessarily impair the correct establishment of pluripotency and the associated metabolic reprogramming. Nonetheless, the occurrence of pathogenic mtDNA modifications might be an important aspect to monitor when characterizing iPSC lines. Finally, we speculate that this random rearrangement of mtDNA molecules might prove beneficial for the derivation of mutation-free iPSCs from patients with mtDNA disorders.

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Metabolic reconfiguration precedes transcriptional regulation in the antioxidant response

Cited by 125 publications

References 9 publications

Regulatory crosstalk of the metabolic network

Regulatory crosstalk of the metabolic network

The role of formate in combatting oxidative stress

Human Induced Pluripotent Stem Cells Harbor Homoplasmic and Heteroplasmic Mitochondrial DNA Mutations While Maintaining Human Embryonic Stem Cell–like Metabolic Reprogramming

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