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A Mathematical Analysis of Aerobic Glycolysis Triggered by Glucose Uptake in Cones.

ABSTRACT: Patients affected by retinitis pigmentosa, an inherited retinal disease, experience a decline in vision due to photoreceptor degeneration leading to irreversible blindness. Rod-derived cone viability factor (RdCVF) is the most promising mutation-independent treatment today. To identify pathologic processes leading to secondary cone photoreceptor dysfunction triggering central vision loss of these patients, we model the stimulation by RdCVF of glucose uptake in cones and glucose metabolism by aerobic glycolysis. We develop a nonlinear system of enzymatic functions and differential equations to mathematically model molecular and cellular interactions in a cone. We use uncertainty and sensitivity analysis to identify processes that have the largest effect on the system and their timeframes. We consider the case of a healthy cone, a cone with low levels of glucose, and a cone with low and no RdCVF. The three key processes identified are metabolism of fructose-1,6-bisphosphate, production of glycerol-3-phosphate and competition that rods exert on cone resources. The first two processes are proportional to the partition of the carbon flux between glycolysis and the pentose phosphate pathway or the Kennedy pathway, respectively. The last process is the rods' competition for glucose, which may explain why rods also provide the RdCVF signal to compensate.

SUBMITTER: Camacho ET

PROVIDER: S-EPMC6411757 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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A Mathematical Analysis of Aerobic Glycolysis Triggered by Glucose Uptake in Cones.

Camacho Erika T ET Brager Danielle D Elachouri Ghizlane G Korneyeva Tatyana T Millet-Puel Géraldine G Sahel José-Alain JA Léveillard Thierry T

Scientific reports 20190311 1

Patients affected by retinitis pigmentosa, an inherited retinal disease, experience a decline in vision due to photoreceptor degeneration leading to irreversible blindness. Rod-derived cone viability factor (RdCVF) is the most promising mutation-independent treatment today. To identify pathologic processes leading to secondary cone photoreceptor dysfunction triggering central vision loss of these patients, we model the stimulation by RdCVF of glucose uptake in cones and glucose metabolism by aer ...[more]

PMID: 30858444

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Project description:IntroductionAggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the "Warburg Effect." It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell.ResultsTo test this hypothesis, we stably transfected lowly glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton-exporting systems: either PMA1 (plasma membrane ATPase 1, a yeast H+-ATPase) or CA-IX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher-grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden.ConclusionsTherefore, cancer cells which increase export of H+ equivalents subsequently increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards an upregulation of aerobic glycolysis, a Warburg phenotype. Overall, we have shown that the traditional understanding of cancer cells favoring glycolysis and the subsequent extracellular acidification is not always linear. Cells which can, independent of metabolism, acidify through proton exporter activity can sufficiently drive their metabolism towards glycolysis providing an important fitness advantage for survival.

Project description:Increased cell senescence contributes to the pathogenesis of aging and aging-related disease. Senescence of human fibroblasts in vitro may be delayed by culture in low glucose concentration. There is also accumulating evidence of senescence delay by exposure to dietary bioactive compounds that activate transcription factor Nrf2. The mechanism of cell senescence delay and connection between these responses is unknown. We describe herein that the cruciferous vegetable-derived metabolite, sulforaphane (SFN), activates Nrf2 and delays senescence of human MRC-5 and BJ fibroblasts in vitro. Cell senescence is associated with a progressive and marked increased rate of glucose metabolism through glycolysis. This increases mitochondrial dysfunction and overwhelms defences against reactive metabolites, leading to increasing proteomic and genomic oxidative damage. Increased glucose entry into glycolysis in fibroblast senescence is mainly mediated by increased hexokinase-2. SFN delayed senescence by decreasing glucose metabolism on the approach to senescence, exhibiting a caloric restriction mimetic-like activity and thereby decreased oxidative damage to cell protein and DNA. This was associated with increased expression of thioredoxin-interacting protein, curbing entry of glucose into cells; decreased hexokinase-2, curbing entry of glucose into cellular metabolism; decreased 6-phosphofructo-2-kinase, downregulating formation of allosteric enhancer of glycolysis fructose-2,6-bisphosphate; and increased glucose-6-phosphate dehydrogenase, downregulating carbohydrate response element- (ChRE-) mediated transcriptional enhancement of glycolysis by Mondo/Mlx. SFN also enhanced clearance of proteins cross-linked by transglutaminase which otherwise increased in senescence. This suggests that screening of compounds to counter senescence-associated glycolytic overload may be an effective strategy to identify compounds with antisenescence activity and health beneficial effects of SFN in longevity may involve delay of senescence through glucose and glycolytic restriction response.

Project description:BackgroundCerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.MethodsHere, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.ResultsSingle-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increased lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggest an E4-associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis.ConclusionsTogether, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a 'Warburg like' endophenotype that is observable in young females decades prior to clinically manifest AD.

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A Mathematical Analysis of Aerobic Glycolysis Triggered by Glucose Uptake in Cones.

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A Mathematical Analysis of Aerobic Glycolysis Triggered by Glucose Uptake in Cones.

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