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Oxygen Supply to Malignant Tumors
Published in Hans-Inge Peterson, Tumor Blood Circulation: Angiogenesis, Vascular Morphology and Blood Flow of Experimental and Human Tumors, 2020
Quite novel findings on the critical role played by the pyruvate kinase in the regulation of glycolysis by respiration (Pasteur effect) and vice versa (Crabtree effect) were reported by Gosalvez and Weinhouse.97
Notes on Cancer
Published in Nate F. Cardarelli, The Thymus in Health and Senescence, 2019
The Crabtree effect is one of several parameters used to develop a malignancy index for human tumors.190 For further information on the energy metabolism of cancerous tissue and the Warburg theory, the readers might add two more references to those cited here.191,192
Outdoor Air Pollution
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
In 1929, Herbert Crabtree used mouse cancer cells to show that when glucose was added to a medium, oxygen consumption decreased.253 Mitochondria were not yet identified as the oxygen-consuming particles, but the iron and cytochrome-containing respiratory catalyst to describe the site of oxygen consumption in cells254 which was later discovered to be mitochondria. The Crabtree effect has been called the inverted Pasteur effect because in the Pasteur effect, exposure to oxygen was found to inhibit anaerobic glycolysis. The magnitude of the respiratory inhibition by glucose caused by the Crabtree effect varies between 5% and 50%255 depending on the cell type and the concentration of glucose added. The Crabtree effect plays an important role in many conditions, including chemical sensitivity and diabetes, in which persistently high levels of calories and glucose produce a relative decrease in mitochondrial oxygen consumption, resulting in weakness and fatigue. There are several biochemical mechanisms that combine to produce the Crabtree effect under conditions of nutrient loading.256 The most significant is the inhibitory effect of the cytosolically produced [ATP]/[ADP][Pk] ratio on mitochondrial ATP synthesis. This happens because mitochondrial oxidative phosphorylation requires cytosolic ADP and Pi to make ATP. When cytosolic ATP rises and ADFP falls, ADP becomes limiting in mitochondria and the excesses of cytosolic ATP inhibits the forward action of mitochondrial ATP synthase (complex V) by classic mechanisms of product inhibition. This induces a chemiosmotic backpressure of protons in the mitochondrial inner membrane space and hyperpolarizes the mitochondrial membrane, that is, makes the mitochondrial membrane potential (Δψm) more negative. Excess electrons that enter mitochondria under these conditions cannot be used to make ATP because of the backpressure. The partial reduction of oxygen to superoxide and peroxide serves as a pressure release valve257 that permits excess electrons to be dissipated and oxygen to be exported from the cell in the form of soluble hydrogen peroxide. All of these biophysical and thermodynamic consequences of nutrient loading result in a net decrease in mitochondrial oxygen consumption that we call the Crabtree effect. This effect explains why fasting periodically for 4–5 days helps right the metabolism's restoring energy to the chemically sensitive or chronic degenerative disease individual. With periodic fasting, even in skipping a meal or fasting for 1–2 days results in a return of energy and sharp brain function and elimination of weakness and fatigue.
Can we mimic skeletal muscles for novel drug discovery?
Published in Expert Opinion on Drug Discovery, 2020
Torie Broer, Alastair Khodabukus, Nenad Bursac
Ideally, the widespread utilization of engineered muscle tissues for drug discovery would require the ability to: (1) replicate known responses to well-characterized pharmaceuticals, (2) accurately predict drug toxicity, (3) faithfully model human disease and predict drug efficacy, and (4) offer relatively low-cost and high-throughput testing capabilities. Engineered human skeletal muscle tissues have been shown to accurately model functional responses to both positive (e.g. IGF-1 and β2 agonists) and negative (e.g. statins, glucocorticoids, and mitochondrial toxins) modulators of muscle function [5]. However, successfully modeling patient-specific myotoxicity or predicting clinical toxicity of novel compounds is likely to require incorporation of liver and intestine tissues to model first-pass drug metabolism as well as additional organs (e.g. fat, endothelium, blood-brain barrier) to predict drug biodistribution, unexpected adverse effects, and organ-organ interactions [7]. The first such ‘human-on-a-chip’ models have already shown success in identifying unanticipated toxicities, including cardiotoxicity driven by bleomycin-induced lung inflammatory factors [8]. Furthermore, the Crabtree Effect, where in vitro cultured cells utilize glycolysis but not oxidative phosphorylation to generate ATP, prevents accurate predication of mitochondrial toxicity, the most common cause of preclinical failure of drug candidates identified from in vitro screens. Shifts to greater oxidative metabolism in engineered muscle tissues could be achieved by decreasing media glucose concentration and adding galactose and/or relevant fatty acids.
Effects of cyclic AMP on the differentiation and bioenergetics of rat C6 glioma cells
Published in International Journal of Neuroscience, 2019
This is the first study to investigate the catabolic metabolism on oxygen consumption rate (OCR) of undifferentiated and five day differentiated C6 glioma cells. Basal O2 consumption of undifferentiated and differentiated C6 glioma cells showed a linear pattern which varied between experiments. Figure 12A showed that basal (ΔO2) at 12 nmol × 107 cells−1 min−1 and 13 nmol × 107 cells−1 min−1 of both undifferentiated and differentiated C6 glioma cells respectively. Earlier studies confirm that basal levels of Oxygen consumption rate were roughly 3 nmol × 107 cells−1 min−1 in MIN6 cell lines [31]. Difference in the basal respiration may be due to the presence of fatty acids in the cells suspensions, the period of time in which the MIN6 cells had been remaining in culture and because the cells were already undergoing apoptosis subsequently consume oxygen [52]. Figure 12B showed that basal lactate production at –3 nmol × 107 cells−1 min−1 and –1.5 nmol × 107 cells−1 min−1 of both undifferentiated and differentiated C6 glioma cells, respectively. This suggests that the differences may be due to drift in the lactate electrode. No previous data had been reported for lactate output in C6 glioma cells. The onefold inhibition in the rate of (ΔO2) produced by 10 mM glucose for both undifferentiated and differentiated C6 glioma cells accompanied by sixfold stimulation in the lactate production for both undifferentiated and differentiated C6 glioma cells. This suggests the adding of glucose was either metabolized solely by glycolysis and apparently not by the TCA, or the cells have marginal oxidative capacity [53]. This may lead to inhibit of oxidative respiration by glycolytic products Crabtree effect [51].
Platelet glycogenolysis is important for energy production and function
Published in Platelets, 2023
Kanakanagavalli Shravani Prakhya, Hemendra Vekaria, Daniёlle M. Coenen, Linda Omali, Joshua Lykins, Smita Joshi, Hammodah R. Alfar, Qing Jun Wang, Patrick Sullivan, Sidney W. Whiteheart
Platelets become highly glycolytic upon activation, increasing lactate production and media acidification. This shift to aerobic glycolysis can rapidly increase the rate of ATP production and is facilitated by the increased glucose influx, as noted above.3 In many cells and tissues, the increased glucose/glycolysis can cause OxPhos (OCR/O2 consumption) to decrease, in a process known as the Crabtree effect which is thought to occur when glycolysis (with NAD+ regeneration) can produce sufficient ATP for function.21 This does not completely explain the response of activated platelets where both ECAR and OCR increase (Figure 6). Metabolomic studies show an increased flux of glucose through the glycolytic pathways upon activation.22 In our studies when glycogenolysis is blocked, OCR is greatly reduced in resting platelets and does not increase upon activation (Figure 6). Our data imply that the metabolic fate of the glucose from platelet glycogen could be through both glycolysis and the TCA cycle (and by extension OxPhos) with a bias toward TCA/OxPhos. Under resting conditions, platelet energy production appears balanced between aerobic glycolysis and TCA/OxPhos. Flux studies have suggested that resting platelets rely on the two sources of ATP, equally.20 Blocking glycogenolysis shifts the balance, increasing lactate production (ECAR) and decreasing OxPhos (OCR; Figure 5). This increased aerobic glycolysis could be compensatory for lost ATP production to rebalance the platelets’ resting state. Upon activation, there is a shift to aerobic glycolysis, likely due to the robust increase in glucose influx via the GLUTs (specifically GLUT3) now mobilized to the platelet plasma membrane from fused α granules. The fate of glycolytic products (i.e., pyruvate) from this pool of glucose may be shifted toward lactate production to regenerate cytosolic NAD+ so that glycolysis can continue. The glycolytic products from the glycogen-derived glucose may be differently routed to the TCA cycle and ultimately to oxidation (OxPhos). Thus, the glycogen pool could act as a reserve to fuel more efficient ATP production via TCA/OxPhos instead of being directed exclusively to the more rapid but less efficient aerobic glycolysis. Similar metabolic routes for glucose have been implied from whole-animal metabolomic experiments.22 In these studies, circulating glucose was acutely metabolized by aerobic glycolysis while the carbons from preloaded glycogen pools went into TCA cycle intermediates. This occurred in several tissues, especially those that normally had glycogen stores, suggesting that these two pools of glucose may have unique metabolic fates.22 Whether this is reflective of an organism-wide control system or intrinsic to specific cells or cell types remains to be defined. Future metabolomic studies will be needed to understand how this is relevant to platelet function.