Myocardial Metabolism During Diabetes Mellitus
Grant N. Pierce, Robert E. Beamish, Naranjan S. Dhalla in Heart Dysfunction in Diabetes, 2019
Puckett and Reddy96 were the first to examine the malate-aspartate shuttle as a function of diabetes. In mitochondria isolated from diabetic animals, they found a decreased rate of incorporation of malate into aspartate and a decreased rate of production of aspartate from glutamate. This would indicate a decrease in the rate of substrate flow through the malateaspartate shuttle. A decrease in the Vmax of the mitochondrial glutamate translocase was also demonstrated in the hearts of diabetic animals.96 Consistent with these findings, other independent researchers found no change in aspartate aminotransferase but a decline in malate dehydrogenase activity in fractions from the diabetic rat heart.97 Obviously, these alterations would limit substrate entry into the mitochondria via the malate-aspartate shuttle and reduce its utilization for the production of ATP through oxidative phosphorylation.
-Glutamate(2-Oxoglutarate) Aminotransferases
Elling Kvamme in Glutamine and Glutamate in Mammals, 1988
The currently accepted malate-aspartate shuttle is shown in Figure 3. Note that gluco-neogenesis in organs, such as the liver, requires a net outflow of malate from the mitochondrion to cytosol.75 In the operation of the malate-aspartate shuttle an inflow of malate is required for the net oxidation of cytosolic NADH. The mitochondrial NAD+ system is more reduced than the cytosolic system in the rat liver.85 Efflux of aspartate from the mitochondrion is an obligatory step in the malate-aspartate shuttle, gluconeogenesis from lactate, and in urea synthesis.86 The translocation of aspartate is by an energy-requiring process.86 In contrast to the glycerol-3-phosphate shuttle a maximum of three ATPs are potentially available for each pair of electrons shuttled across the membrane via the malate-aspartate shuttle.
Experimental and Clinical States of Hyperammonia: Alterations in Glutamate and Glutamine
Elling Kvamme in Glutamine and Glutamate in Mammals, 1988
The acute administration of ammonium salts to rats and dogs with portasystemic shunts caused lethargy, coma, and EEG changes similar to those of hepatic coma.7,8,12 In shunted dogs and humans, the same occurred with a large protein load.12,15,71 Similar results followed urease injection or the ingestion of urea in dogs.12 In rats with shunts, the additional ammonium load elevated the brain ammonia and glutamine further.7,8 Brain aspartate and glutamate decreased; alanine and asparagine increased; and GABA remained unchanged.8 When rats with portacaval anastomoses were given the additional ammonia, cerebral blood flow and oxygen utilization declined, the lactate/pyruvate concentration ratio in the brain increased, and the NAD+/NADH concentration ratio and ATP concentration declined.7,8 These abnormalities may all be due to a failure to oxidize cytoplasmic NADH. NADH cannot diffuse into mitochondria, so reducing equivalents must be transported by the malate/ aspartate shuttle. If glutamate is converted to glutamine during ammonia metabolism, it may not be available to exchange for aspartate in the shuttle. Indeed, isolated brain mitochondria could not function without all the intermediates of this shuttle being present in the culture medium.72
Changes of hippocampus proteomic profiles after blueberry extracts supplementation in APP/PS1 transgenic mice
Published in Nutritional Neuroscience, 2020
Hai-qiang Li, Long Tan, Hong-peng Yang, Wei Pang, Tong Xu, Yu-gang Jiang
MDH is an enzyme that catalyzes the last step of the citric acid cycle, the reversible oxidation of malate to oxaloacetate coupled with the reduction of NAD+ to NADH. MDH is located in both the cytosol and the mitochondrial matrix and participates in the malate-aspartate shuttle that passively feeds electrons from cytosolic NADH into the electron transport chain. Loss-of-function of MDH due to oxidative modification would significantly decrease the efficiency of the citric acid cycle as well as the transport of electrons from cytosolic NADH into the mitochondrial matrix, and consequently, decrease the production of ATP.42 MDH was markedly increased in Early Alzheimer’s disease (EAD).43 In our study, the down-regulated expression of MDH might associate with the improving of energy dysfunction.
Exploratory metabolomic analysis based on UHPLC-Q-TOF-MS/MS to study hypoxia-reoxygenation energy metabolic alterations in HK-2 cells
Published in Renal Failure, 2023
Xiaoyu Yang, Ailing Kang, Yuanyue Lu, Yafeng Li, Lili Guo, Rongshan Li, Xiaoshuang Zhou
With the increase in reoxygenation time, the content of most amino acids in HK-2 cells showed an increasing trend and reached a peak at 12h. Notably, the arginine content decreased and reached a trough at 12 h of reoxygenation, in contrast to the trend of the other amino acid contents. Glutamate (Figure 5(A,B)) is one of the kidney’s most important substrates for ammonia production and plays an important role in acid-base homeostasis. HK-2 cells’ mitochondria can oxidize glutamate to α-ketoglutarate, which enters the TCA cycle via transamination and is further converted to succinate, which is used to supplement the impaired TCA cycle [12]. Aspartic acid and arginine (Figure 5(C,D)) were involved in the urea cycle and transported NAD + transport into mitochondria with the malate–aspartate shuttle, which was involved in the tricarboxylic acid cycle, glycolysis, and the electron transport chain [13,14]. In the cells of proximal renal tubules, arginine synthetase acts on citrulline to produce arginine [15]. But the trend of arginine is opposite to that of aspartic acid. The probable cause is a decrease in renal arginine production during unilateral ischemia-reperfusion, a change that may facilitate the recovery of low plasma arginine levels after trauma, shock, or vascular surgery [16]. Transcription factor Krüppel-like factor 6 (KLF6) was strongly induced after AKI. KLF6-mediated inhibition of BCAA catabolism can lead to increased BCAA levels such as Leucylleucine (Figure 5(E)) [17]. D-proline accumulates during renal insufficiency, and proline induces oxidative stress and lipid peroxidation in rat kidneys [18,19]. It has been shown that the greatest fluctuations in amino acid metabolism among metabolic pathways were observed in a renal ischemia-reperfusion model, suggesting that amino acid metabolism may be a significant but unnoticed pathway in the development of IR-AKI [20].
The application of proteomics in muscle exercise physiology
Published in Expert Review of Proteomics, 2020
Stuart J Hesketh, Ben N Stansfield, Connor A Stead, Jatin G Burniston
Mitochondrial samples from HCR/LCR muscle were also enriched for phosphorylated or acetylated peptides and differences in modification status were investigated by LC-MS/MS analysis of TMT-labeled samples [28]. Acetylation rather than phosphorylation emerged as the most prominent difference between HCR and LCR mitochondria. Numerous proteins were less acetylated in HCR than LCR, and the acetylation of some proteins decreased further in HCR mitochondria after exercise. Differences in the acetylation of mitochondrial enzymes were not associated with the abundance of sirtuin-3 deacetylase and may, instead, reflect differences in NAD/NADH ratio in the mitochondria of high- versus low-capacity runners. Mitochondrial malate dehydrogenase (MDHM) emerged as a key enzyme that may be regulated by acetylation. K335 acetylation of MDHM was significantly less in HCR than LCR mitochondria, and K239 acetylation of MDHM decreased significantly after 10 min aerobic exercise specifically in HCR mitochondria. Coincidently, Souza et al. [29] reports reversible oxidation of cysteine residues in HCR and LCR plantaris muscle and found significantly greater oxidation of C137/C154 of cytoplasmic malate dehydrogenase (MDHC) in HCR. In both Overmyer et al. [28] and Souza et al. [29] the post-translation modification of malate dehydrogenase isoforms were associated with greater enzymatic activity, which is consistent with a greater capacity to exchange reducing equivalents via the malate-aspartate shuttle in HCR skeletal muscle. These findings are consistent with human muscle responses to exercise in diabetic patients, which also included gains in the abundance of enzymes of the malate-aspartate shuttle [30]. Overall, the recent proteomic analyses of mitochondria-enriched muscle fractions suggest adaptations to aerobic training are more intricate than a general upward shift in muscle mitochondrial content.
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