scholarly journals Inborn disorders of the Malate Aspartate Shuttle

2021 ◽  
Author(s):  
Melissa H. Broeks ◽  
Clara D.M. van Karnebeek ◽  
Ronald J.A. Wanders ◽  
Judith J.M. Jans ◽  
Nanda M. Verhoeven‐Duif
Keyword(s):  
Malate Aspartate Shuttle

scholarly journals PIK3CAmutant tumors depend on oxoglutarate dehydrogenase

2017 ◽  
Vol 114 (17) ◽  
pp. E3434-E3443 ◽  
Author(s):  
Nina Ilic ◽  
Kıvanç Birsoy ◽  
Andrew J. Aguirre ◽  
Nora Kory ◽  
Michael E. Pacold ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Glucose Metabolism ◽  
Cancer Cell ◽  
Mutant Cell ◽  
Tca Cycle ◽  
Loss Of Function ◽  
Cycle Enzyme ◽  
Oxoglutarate Dehydrogenase ◽  
Mutant Cells ◽  
Malate Aspartate Shuttle

OncogenicPIK3CAmutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found thatPIK3CAmutant cancer cells requirePIK3CAbut also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustainPIK3CAmutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy withinPIK3CAmutant cells. Reduced levels of aspartate deregulated the malate–aspartate shuttle, which is important for cytoplasmic NAD+regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, becausePIK3CAmutant cells exhibit a profound reliance on glucose metabolism, malate–aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD+/NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene.

Effects of calmodulin antagonists on hydrogen-translocating shuttles in perfused rat liver

1991 ◽  
Vol 261 (3) ◽  
pp. E325-E331 ◽  
Author(s):  
Y. Hamatani ◽  
M. Inoue ◽  
K. Kimura ◽  
M. Shiota ◽  
M. Ohta ◽  
...  
Keyword(s):  
Rat Liver ◽  
Perfused Rat Liver ◽  
Calmodulin Antagonists ◽  
Glycerophosphate Dehydrogenase ◽  
Malate Aspartate Shuttle ◽  
Oxidation Of Ethanol ◽  
Adrenalectomized Rats ◽  
Intact Rats

The effects of calmodulin antagonists on the capacity of hydrogen-translocating shuttles were studied in the perfused rat liver. The capacity was estimated by measuring the changes in the rate of production of glucose from sorbitol during the oxidation of ethanol [T. Sugano, T. Ohta, A. Tarui, and Y. Miyamae. Am. J. Physiol. 251 (Endocrinol. Metab. 14): E385-E392, 1986]. Thyroxine given to intact rats increased the activity of alpha-glycerophosphate dehydrogenase (alpha-GPD). Glucocorticoid replacement in adrenalectomized rats decreased the activity of the alpha-GPD to values obtained after treatment with PTU. In either thyroxine-treated or steroid-replaced rats, the capacity of hydrogen-translocating shuttles increased markedly. However, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), trifluoperazine, and chlorpromazine inhibited the increased capacity in steroid-replaced rats and had no effect on the increased capacity in thyroxine-treated rats. W-7 inhibited the stimulatory effects of norepinephrine on the capacity of the malate-aspartate shuttle without inhibition of efflux of intracellular Ca2+. The stimulatory effects of vasopressin on the malate-aspartate shuttle were also inhibited by W-7, trifluoperazine, and chlorpromazine. The results suggest that the malate-aspartate shuttle may be regulated by Ca(2+)-calmodulin.

scholarly journals GLUL Ablation Can Confer Drug Resistance to Cancer Cells via a Malate-Aspartate Shuttle-Mediated Mechanism

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1945
Author(s):  
Magesh Muthu ◽  
Ranjeet Kumar ◽  
Azharuddin Sajid Syed Khaja ◽  
Jonathan D. Gilthorpe ◽  
Jenny L. Persson ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Cell Lines ◽  
Small Cell Lung Carcinoma ◽  
A549 Cells ◽  
Cancer Drug ◽  
Aminooxyacetic Acid ◽  
Cell Lung Carcinoma ◽  
Metabolic Fitness ◽  
Malate Aspartate Shuttle

Glutamate-ammonia ligase (GLUL) is important for acid-base homeostasis, ammonia detoxification, cell signaling, and proliferation. Here, we reported that GLUL ablation conferred resistance to several anticancer drugs in specific cancer cell lines while leaving other cell lines non-resistant to the same drugs. To understand the biochemical mechanics supporting this drug resistance, we compared drug-resistant GLUL knockout (KO) A549 non-small-cell lung carcinoma (NSCLC) cells with non-resistant GLUL KO H1299 NSCLC cells and found that the resistant A549 cells, to a larger extent, depended on exogenous glucose for proliferation. As GLUL activity is linked to the tricarboxylic acid (TCA) cycle via reversed glutaminolysis, we probed carbon flux through both glycolysis and TCA pathways by means of 13C5 glutamine, 13C5 glutamate, and 13C6 glucose tracing. We observed increased labeling of malate and aspartate in A549 GLUL KO cells, whereas the non-resistant GLUL KO H1299 cells displayed decreased 13C-labeling. The malate and aspartate shuttle supported cellular NADH production and was associated with cellular metabolic fitness. Inhibition of the malate-aspartate shuttle with aminooxyacetic acid significantly impacted upon cell viability with an IC50 of 11.5 μM in resistant GLUL KO A549 cells compared to 28 μM in control A549 cells, linking resistance to the malate-aspartate shuttle. Additionally, rescuing GLUL expression in A549 KO cells increased drug sensitivity. We proposed a novel metabolic mechanism in cancer drug resistance where the increased capacity of the malate-aspartate shuttle increased metabolic fitness, thereby facilitating cancer cells to escape drug pressure.

MDH1 deficiency is a metabolic disorder of the malate–aspartate shuttle associated with early onset severe encephalopathy

2019 ◽  
Vol 138 (11-12) ◽  
pp. 1247-1257 ◽  
Author(s):  
Melissa H. Broeks ◽  
Hanan E. Shamseldin ◽  
Amal Alhashem ◽  
Mais Hashem ◽  
Firdous Abdulwahab ◽  
...  
Keyword(s):  
Early Onset ◽  
Metabolic Disorder ◽  
Malate Aspartate Shuttle
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