Oxaloacetate Mediates Mitochondrial Metabolism and Function

Author(s): Liping Yu*, William I. Sivitz*

Journal Name: Current Metabolomics and Systems Biology
Formerly Current Metabolomics

Volume 7 , Issue 1 , 2020

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Graphical Abstract:


Abstract:

Oxaloacetate, an intermediate in the tricarboxylic acid cycle, plays important roles in regulating mitochondrial function, gluconeogenesis, the urea cycle, and amino acid syntheses. Because this compound is not stable, more information is needed about its stability profile before its medicinal potential can be realized. In this short review, we present current knowledge and understanding of oxaloacetate with a focus on its stability, degradation, quantification methods, regulation of mitochondrial function, and potential therapeutic benefits. Further, we report previously unpublished spectral data related to the stability profile of oxaloacetate. We found that oxaloacetate has a half-life of about 14 hours in biological aqueous solution at 25°C before degrading into pyruvate. This mandates careful attention to handling this compound including storage at -20 to -80°C when not in use to prolong its shelf-life. Also, the oxaloacetate stability profile needs to be taken into account when conducting experiments involving the compound either in clinical trials or evaluating it as a health supplement or for other experiments. Measuring oxaloacetate by mass-spectrometry requires cumbersome derivatization to assure stability. However, we found that NMR can be used to detect oxaloacetate quantitatively without the need for making derivatives, and the NMR method is sensitive enough to detect oxaloacetate in the micromolar range. Using this method, we showed that oxaloacetate regulates mitochondrial complex II-driven respiration by potent inhibition of succinate dehydrogenase. Moreover, a growing literature in the past few years suggests that oxaloacetate may have therapeutic benefits in treating a variety of diseases.

Keywords: Oxaloacetic acid, oxaloacetate, NMR, mitochondrial metabolism, mitochondria, bioenergetics, respiration.

[1]
Lowenstein, J.M. Methods in Enzymology Citric Acid Cycle; Academic Press: Boston, 1969, p. 13.
[2]
Thauer, R.K. Citric-acid cycle, 50 years on. Modifications and an alternative pathway in anaerobic bacteria. Eur. J. Biochem., 1988, 176(3), 497-508.
[http://dx.doi.org/10.1111/j.1432-1033.1988.tb14307.x] [PMID: 3049083]
[3]
Minárik, P.; Tomásková, N.; Kollárová, M.; Antalík, M. Malate dehydrogenases--structure and function. Gen. Physiol. Biophys., 2002, 21(3), 257-265.
[PMID: 12537350]
[4]
Musrati, R.A.; Kollárová, M.; Mernik, N.; Mikulásová, D. Malate dehydrogenase: distribution, function and properties. Gen. Physiol. Biophys., 1998, 17(3), 193-210.
[PMID: 9834842]
[5]
Jitrapakdee, S.; St Maurice, M.; Rayment, I.; Cleland, W.W.; Wallace, J.C.; Attwood, P.V. Structure, mechanism and regulation of pyruvate carboxylase. Biochem. J., 2008, 413(3), 369-387.
[http://dx.doi.org/10.1042/BJ20080709] [PMID: 18613815]
[6]
Adina-Zada, A.; Zeczycki, T.N.; St Maurice, M.; Jitrapakdee, S.; Cleland, W.W.; Attwood, P.V. Allosteric regulation of the biotin-dependent enzyme pyruvate carboxylase by acetyl-CoA. Biochem. Soc. Trans., 2012, 40(3), 567-572.
[http://dx.doi.org/10.1042/BST20120041] [PMID: 22616868]
[7]
Valle, M. Macromolecular Protein Complexes: Structure and Function; Harris, J.R.; Marles-Wright, J., Eds.;. Springer International Publishing: Cham, , 2017, pp. 291-322.
[http://dx.doi.org/10.1007/978-3-319-46503-6_11]
[8]
Holt, M.C.; Assar, Z.; Beheshti Zavareh, R.; Lin, L.; Anglin, J.; Mashadova, O.; Haldar, D.; Mullarky, E.; Kremer, D.M.; Cantley, L.C.; Kimmelman, A.C.; Stein, A.J.; Lairson, L.L.; Lyssiotis, C.A. Biochemical characterization and structure-based mutational analysis provide insight into the binding and mechanism of action of novel aspartate aminotransferase inhibitors. Biochemistry, 2018, 57(47), 6604-6614.
[http://dx.doi.org/10.1021/acs.biochem.8b00914] [PMID: 30365304]
[9]
Han, Q.; Robinson, H.; Cai, T.; Tagle, D.A.; Li, J. Biochemical and structural characterization of mouse mitochondrial aspartate aminotransferase, a newly identified kynurenine aminotransferase-IV. Biosci. Rep., 2011, 31(5), 323-332.
[http://dx.doi.org/10.1042/BSR20100117] [PMID: 20977429]
[10]
Murakami, M.; Kouyama, T. Crystal structures of two isozymes of citrate synthase from sulfolobus tokodaii strain 7. Biochem. Res. Int., 2016, 20167560919
[http://dx.doi.org/10.1155/2016/7560919] [PMID: 27656296]
[11]
Karpusas, M.; Branchaud, B.; Remington, S.J. Proposed mechanism for the condensation reaction of citrate synthase: 1.9-A structure of the ternary complex with oxaloacetate and carboxymethyl coenzyme A. Biochemistry, 1990, 29(9), 2213-2219.
[http://dx.doi.org/10.1021/bi00461a002] [PMID: 2337600]
[12]
Hanson, R.W.; Reshef, L. Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annu. Rev. Biochem., 1997, 66(1), 581-611.
[http://dx.doi.org/10.1146/annurev.biochem.66.1.581] [PMID: 9242918]
[13]
Weiss, A.K.H.; Naschberger, A.; Loeffler, J.R.; Gstach, H.; Bowler, M.W.; Holzknecht, M.; Cappuccio, E.; Pittl, A.; Etemad, S.; Dunzendorfer-Matt, T.; Scheffzek, K.; Liedl, K.R.; Jansen-Dürr, P. Structural basis for the bi-functionality of human oxaloacetate decarboxylase FAHD1. Biochem. J., 2018, 475(22), 3561-3576.
[http://dx.doi.org/10.1042/BCJ20180750] [PMID: 30348641]
[14]
Haines, R.J.; Pendleton, L.C.; Eichler, D.C. Argininosuccinate synthase: at the center of arginine metabolism. Int. J. Biochem. Mol. Biol., 2011, 2(1), 8-23.
[PMID: 21494411]
[15]
Shambaugh, G.E. III Urea biosynthesis I. The urea cycle and relationships to the citric acid cycle. Am. J. Clin. Nutr., 1977, 30(12), 2083-2087.
[http://dx.doi.org/10.1093/ajcn/30.12.2083] [PMID: 337792]
[16]
Lehninger, A.L.; Nelson, D.L.; Cox, M.M. Principles of Biochemistry, 3rd ed; W. H. Freeman: New York, 2000.
[17]
Bai, F.; Fink, B.D.; Yu, L.; Sivitz, W.I. Voltage-dependent regulation of complex II energized mitochondrial oxygen flux. PLoS One, 2016, 11(5): e0154982
[http://dx.doi.org/10.1371/journal.pone.0154982] [PMID: 27153112]
[18]
Fink, B.D.; Bai, F.; Yu, L.; Sheldon, R.D.; Sharma, A.; Taylor, E.B.; Sivitz, W.I. Oxaloacetic acid mediates ADP-dependent inhibition of mitochondrial complex II-driven respiration. J. Biol. Chem., 2018, 293(51), 19932-19941.
[http://dx.doi.org/10.1074/jbc.RA118.005144] [PMID: 30385511]
[19]
Schollmeyer, P.; Klingenberg, M. Oxaloacetate and adenosinetriphosphate levels during inhibition and activation of succinate oxidation. Biochem. Biophys. Res. Commun., 1961, 4(1), 43-47.
[http://dx.doi.org/10.1016/0006-291X(61)90252-2] [PMID: 13748457]
[20]
Brekke, E.; Walls, A.B.; Nørfeldt, L.; Schousboe, A.; Waagepetersen, H.S.; Sonnewald, U. Direct measurement of backflux between oxaloacetate and fumarate following pyruvate carboxylation. Glia, 2012, 60(1), 147-158.
[http://dx.doi.org/10.1002/glia.21265] [PMID: 22052553]
[21]
Zimmermann, M.; Sauer, U.; Zamboni, N. Quantification and mass isotopomer profiling of α-keto acids in central carbon metabolism. Anal. Chem., 2014, 86(6), 3232-3237.
[http://dx.doi.org/10.1021/ac500472c] [PMID: 24533614]
[22]
Al Kadhi, O.; Melchini, A.; Mithen, R.; Saha, S. Development of a LC-MS/MS method for the simultaneous detection of tricarboxylic acid cycle intermediates in a range of biological matrices. J. Anal. Methods Chem., 2017, 2017: 5391832
[http://dx.doi.org/10.1155/2017/5391832] [PMID: 29075551]
[23]
Walvekar, A.; Rashida, Z.; Maddali, H.; Laxman, S. A versatile LC-MS/MS approach for comprehensive, quantitative analysis of central metabolic pathways. Wellcome Open Res., 2018, 3(122), 122.
[http://dx.doi.org/10.12688/wellcomeopenres.14832.1] [PMID: 30345389]
[24]
Tan, B.; Lu, Z.; Dong, S.; Zhao, G.; Kuo, M-S. Derivatization of the tricarboxylic acid intermediates with O-benzylhydroxylamine for liquid chromatography-tandem mass spectrometry detection. Anal. Biochem., 2014, 465, 134-147.
[http://dx.doi.org/10.1016/j.ab.2014.07.027] [PMID: 25102203]
[25]
Palmer, A.G.; Cavanagh, J.; Wright, P.E.; Rance, M. Sensitivity improvement in proton-detected two-dimensional heteronuclear correlation NMR spectroscopy. J. Magn. Reson., 1991, 93(1), 151-170.
[26]
Delaglio, F.; Grzesiek, S.; Vuister, G.W.; Zhu, G.; Pfeifer, J.; Bax, A. NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J. Biomol. NMR, 1995, 6(3), 277-293.
[http://dx.doi.org/10.1007/BF00197809] [PMID: 8520220]
[27]
Johnson, B.A.; Blevins, R.A.; N.M.R., View A computer program for the visualization and analysis of NMR data. J. Biomol. NMR, 1994, 4(5), 603-614.
[http://dx.doi.org/10.1007/BF00404272] [PMID: 22911360]
[28]
Lee, W.; Tonelli, M.; Markley, J.L. NMRFAM-SPARKY: enhanced software for biomolecular NMR spectroscopy. Bioinformatics, 2015, 31(8), 1325-1327.
[http://dx.doi.org/10.1093/bioinformatics/btu830] [PMID: 25505092]
[29]
Chance, B.; Hagihara, B. Activation and inhibition of succinate oxidation following adenosine diphosphate supplements to pigeon heart mitochondria. J. Biol. Chem., 1962, 237(11), 3540-3545.
[PMID: 14019996]
[30]
Wojtczak, A.B.; Wojtczak, L. The effect of oxalacetate on the oxidation of succinate of in liver mitochondria. Biochim. Biophys. Acta, 1964, 89(3), 560-563.
[PMID: 14216061]
[31]
Azzone, G.F.; Ernster, L.; Klingenberg, M. Energetic aspects of the mitochondrial oxidation of succinate. Nature, 1960, 188(4750), 552-555.
[http://dx.doi.org/10.1038/188552a0] [PMID: 13685479]
[32]
Panov, A.V.; Vavilin, V.A.; Lyakhovich, V.V.; Brooks, B.R.; Bonkovsky, H.L. Effect of bovine serum albumin on mitochondrial respiration in the brain and liver of mice and rats. Bull. Exp. Biol. Med., 2010, 149(2), 187-190.
[http://dx.doi.org/10.1007/s10517-010-0904-5] [PMID: 21113488]
[33]
Panov, A.V.; Kubalik, N.; Zinchenko, N.; Ridings, D.M.; Radoff, D.A.; Hemendinger, R.; Brooks, B.R.; Bonkovsky, H.L. Metabolic and functional differences between brain and spinal cord mitochondria underlie different predisposition to pathology. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2011, 300(4), R844-R854.
[http://dx.doi.org/10.1152/ajpregu.00528.2010] [PMID: 21248309]
[34]
Masuoka, J.; Hegenauer, J.; Van Dyke, B.R.; Saltman, P. Intrinsic stoichiometric equilibrium constants for the binding of zinc(II) and copper(II) to the high affinity site of serum albumin. J. Biol. Chem., 1993, 268(29), 21533-21537.
[PMID: 8408004]
[35]
Nafisi, S.; Bagheri Sadeghi, G. PanahYab, A. Interaction of aspirin and vitamin C with bovine serum albumin. J. Photochem. Photobiol. B, 2011, 105(3), 198-202.
[http://dx.doi.org/10.1016/j.jphotobiol.2011.09.002] [PMID: 21995892]
[36]
Ghosh, S.; Dey, J. Binding of fatty acid amide amphiphiles to bovine serum albumin: role of amide hydrogen bonding. J. Phys. Chem. B, 2015, 119(25), 7804-7815.
[http://dx.doi.org/10.1021/acs.jpcb.5b00965] [PMID: 26023820]
[37]
Zhang, L.; Cai, Q-Y.; Cai, Z-X.; Fang, Y.; Zheng, C-S.; Wang, L-L.; Lin, S.; Chen, D-X.; Peng, J. Interactions of bovine serum albumin with anti-cancer compounds using a ProteOn XPR36 array biosensor and molecular docking. Molecules, 2016, 21(12), 1706.
[http://dx.doi.org/10.3390/molecules21121706] [PMID: 27973422]
[38]
Pathak, M.; Mishra, R.; Agarwala, P.K.; Ojha, H.; Singh, B.; Singh, A.; Kukreti, S. Binding of ethyl pyruvate to bovine serum albumin: Calorimetric, spectroscopic and molecular docking studies. Thermochim. Acta, 2016, 633, 140-148.
[http://dx.doi.org/10.1016/j.tca.2016.04.006]
[39]
Fink, B.D.; Yu, L.; Sivitz, W.I. Modulation of complex II-energized respiration in muscle, heart, and brown adipose mitochondria by oxaloacetate and complex I electron flow. FASEB J., 2019. 33fj201900690R Epub ahead of print
[http://dx.doi.org/10.1096/fj.201900690R] [PMID: 31361970]
[40]
Chen, J-Q.; Russo, J. Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochim. Biophys. Acta, 2012, 1826(2), 370-384.
[PMID: 22750268]
[41]
Schlichtholz, B.; Turyn, J.; Goyke, E.; Biernacki, M.; Jaskiewicz, K.; Sledzinski, Z.; Swierczynski, J. Enhanced citrate synthase activity in human pancreatic cancer. Pancreas, 2005, 30(2), 99-104.
[http://dx.doi.org/10.1097/01.mpa.0000153326.69816.7d] [PMID: 15714131]
[42]
Rustin, P.; Bourgeron, T.; Parfait, B.; Chretien, D.; Munnich, A.; Rötig, A. Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human. Biochim. Biophys. Acta, 1997, 1361(2), 185-197.
[http://dx.doi.org/10.1016/S0925-4439(97)00035-5] [PMID: 9300800]
[43]
Ait-El-Mkadem, S.; Dayem-Quere, M.; Gusic, M.; Chaussenot, A.; Bannwarth, S.; François, B.; Genin, E.C.; Fragaki, K.; Volker-Touw, C.L.M.; Vasnier, C.; Serre, V.; van Gassen, K.L.I.; Lespinasse, F.; Richter, S.; Eisenhofer, G.; Rouzier, C.; Mochel, F.; De Saint-Martin, A.; Abi Warde, M-T.; de Sain-van der Velde, M.G.M.; Jans, J.J.M.; Amiel, J.; Avsec, Z.; Mertes, C.; Haack, T.B.; Strom, T.; Meitinger, T.; Bonnen, P.E.; Taylor, R.W.; Gagneur, J.; van Hasselt, P.M.; Rötig, A.; Delahodde, A.; Prokisch, H.; Fuchs, S.A.; Paquis-Flucklinger, V. Mutations in MDH2, encoding a Krebs cycle enzyme, cause early-onset severe encephalopathy. Am. J. Hum. Genet., 2017, 100(1), 151-159.
[http://dx.doi.org/10.1016/j.ajhg.2016.11.014] [PMID: 27989324]
[44]
Guo, C.; Sun, L.; Chen, X.; Zhang, D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen. Res., 2013, 8(21), 2003-2014.
[PMID: 25206509]
[45]
Kausar, S.; Wang, F.; Cui, H. The role of mitochondria in reactive oxygen species generation and its implications for neurodegenerative diseases. Cells, 2018, 7(12), 274.
[http://dx.doi.org/10.3390/cells7120274] [PMID: 30563029]
[46]
Panov, A.; Schonfeld, P.; Dikalov, S.; Hemendinger, R.; Bonkovsky, H.L.; Brooks, B.R. The neuromediator glutamate, through specific substrate interactions, enhances mitochondrial ATP production and reactive oxygen species generation in nonsynaptic brain mitochondria. J. Biol. Chem., 2009, 284(21), 14448-14456.
[http://dx.doi.org/10.1074/jbc.M900985200] [PMID: 19304986]
[47]
Williams, D.S.; Cash, A.; Hamadani, L.; Diemer, T. Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway. Aging Cell, 2009, 8(6), 765-768.
[http://dx.doi.org/10.1111/j.1474-9726.2009.00527.x] [PMID: 19793063]
[48]
Hipkiss, A.R. Proteotoxicity and the contrasting effects of oxaloacetate and glycerol on Caenorhabditis elegans life span: a role for methylglyoxal? Rejuvenation Res., 2010, 13(5), 547-551.
[http://dx.doi.org/10.1089/rej.2010.1025] [PMID: 20645869]
[49]
Cash, A. Oxaloacetic acid supplementation as a mimic of calorie restriction. Open Longev. Sci., 2009, 3, 22-27.
[http://dx.doi.org/10.2174/1876326X00903010022]
[50]
Ruban, A.; Mohar, B.; Jona, G.; Teichberg, V.I. Blood glutamate scavenging as a novel neuroprotective treatment for paraoxon intoxication. J. Cereb. Blood Flow Metab., 2014, 34(2), 221-227.
[http://dx.doi.org/10.1038/jcbfm.2013.186] [PMID: 24149933]
[51]
Campos, F.; Sobrino, T.; Ramos-Cabrer, P.; Argibay, B.; Agulla, J.; Pérez-Mato, M.; Rodríguez-González, R.; Brea, D.; Castillo, J. Neuroprotection by glutamate oxaloacetate transaminase in ischemic stroke: an experimental study. J. Cereb. Blood Flow Metab., 2011, 31(6), 1378-1386.
[http://dx.doi.org/10.1038/jcbfm.2011.3] [PMID: 21266983]
[52]
Nagy, D.; Marosi, M.; Kis, Z.; Farkas, T.; Rakos, G.; Vecsei, L.; Teichberg, V.I.; Toldi, J. Oxaloacetate decreases the infarct size and attenuates the reduction in evoked responses after photothrombotic focal ischemia in the rat cortex. Cell. Mol. Neurobiol., 2009, 29(6-7), 827-835.
[http://dx.doi.org/10.1007/s10571-009-9364-8] [PMID: 19259807]
[53]
Yamamoto, H.A.; Mohanan, P.V. Effect of α-ketoglutarate and oxaloacetate on brain mitochondrial DNA damage and seizures induced by kainic acid in mice. Toxicol. Lett., 2003, 143(2), 115-122.
[http://dx.doi.org/10.1016/S0378-4274(03)00114-0] [PMID: 12749815]
[54]
Zlotnik, A.; Sinelnikov, I.; Gruenbaum, B.F.; Gruenbaum, S.E.; Dubilet, M.; Dubilet, E.; Leibowitz, A.; Ohayon, S.; Regev, A.; Boyko, M.; Shapira, Y.; Teichberg, V.I. Effect of glutamate and blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome and pathohistology of the hippocampus after traumatic brain injury in rats. Anesthesiology, 2012, 116(1), 73-83.
[http://dx.doi.org/10.1097/ALN.0b013e31823d7731] [PMID: 22129535]
[55]
Li, Y.; Hou, X.; Qi, Q.; Wang, L.; Luo, L.; Yang, S.; Zhang, Y.; Miao, Z.; Zhang, Y.; Wang, F.; Wang, H.; Huang, W.; Wang, Z.; Shen, Y.; Wang, Y. Scavenging of blood glutamate for enhancing brain-to-blood glutamate efflux. Mol. Med. Rep., 2014, 9(1), 305-310.
[http://dx.doi.org/10.3892/mmr.2013.1793] [PMID: 24220720]
[56]
Boyko, M.; Melamed, I.; Gruenbaum, B.F.; Gruenbaum, S.E.; Ohayon, S.; Leibowitz, A.; Brotfain, E.; Shapira, Y.; Zlotnik, A. The effect of blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome in a rat model of subarachnoid hemorrhage. Neurotherapeutics, 2012, 9(3), 649-657.
[http://dx.doi.org/10.1007/s13311-012-0129-6] [PMID: 22711471]
[57]
Kuang, Y.; Han, X.; Xu, M.; Wang, Y.; Zhao, Y.; Yang, Q. Oxaloacetate ameliorates chemical liver injury via oxidative stress reduction and enhancement of bioenergetic fluxes. Int. J. Mol. Sci., 2018, 19(6), 1626.
[http://dx.doi.org/10.3390/ijms19061626] [PMID: 29857490]
[58]
Sawa, K.; Uematsu, T.; Korenaga, Y.; Hirasawa, R.; Kikuchi, M.; Murata, K.; Zhang, J.; Gai, X.; Sakamoto, K.; Koyama, T.; Satoh, T. Krebs cycle intermediates protective against oxidative stress by modulating the level of reactive oxygen species in neuronal HT22 cells. Antioxidants, 2017, 6(1), 21.
[http://dx.doi.org/10.3390/antiox6010021] [PMID: 28300753]
[59]
Wilkins, H.M.; Koppel, S.; Carl, S.M.; Ramanujan, S.; Weidling, I.; Michaelis, M.L.; Michaelis, E.K.; Swerdlow, R.H. Oxaloacetate enhances neuronal cell bioenergetic fluxes and infrastructure. J. Neurochem., 2016, 137(1), 76-87.
[http://dx.doi.org/10.1111/jnc.13545] [PMID: 26811028]
[60]
Wilkins, H.M. Harris, J.L.; Carl, S.M.; e, L.; Lu, J.; Eva Selfridge, J.; Roy, N.; Hutfles, L.; Koppel, S.; Morris, J.; Burns, J.M.; Michaelis, M.L.; Michaelis, E.K.; Brooks, W.M.; Swerdlow, R.H. Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. Hum. Mol. Genet., 2014, 23(24), 6528-6541.
[http://dx.doi.org/10.1093/hmg/ddu371] [PMID: 25027327]
[61]
Ruban, A.; Berkutzki, T.; Cooper, I.; Mohar, B.; Teichberg, V.I. Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas. Invest. New Drugs, 2012, 30(6), 2226-2235.
[http://dx.doi.org/10.1007/s10637-012-9794-x] [PMID: 22392507]
[62]
Yoshikawa, K. Studies on the anti-diabetic effect of sodium oxaloacetate. Tohoku J. Exp. Med., 1968, 96(2), 127-141.
[http://dx.doi.org/10.1620/tjem.96.127] [PMID: 4884771]
[63]
Swerdlow, R.H.; Bothwell, R.; Hutfles, L.; Burns, J.M.; Reed, G.A. Tolerability and pharmacokinetics of oxaloacetate 100 mg capsules in Alzheimer’s subjects. BBA Clin., 2016, 5, 120-123.
[http://dx.doi.org/10.1016/j.bbacli.2016.03.005] [PMID: 27051598]
[64]
Swerdlow, R.H. Bioenergetics and metabolism: a bench to bedside perspective. J. Neurochem., 2016, 139(S2)(Suppl. 2), 126-135.
[http://dx.doi.org/10.1111/jnc.13509] [PMID: 26968700]
[65]
Swerdlow, R.H.; Lyons, K.E.; Khosla, S.K.; Nashatizadeh, M.; Pahwa, R.A. A pilot study of oxaloacetate 100 mg capsules in Parkinson’s disease patients. J. Parkinsons Dis. Alzheimers Dis., 2016, 3(2), 4.
[66]
Vidoni, E.D.; Clutton, J.; Becker, A.M.; Sherry, E.; Bothwell, R.; Mahnken, J.D.; Wilkins, H.M.; Lee, P.; Choi, I-Y.; Brooks, W.; Reed, G.; Burns, J.M.; Swerdlow, R.H. Trial of oxaloacetate in Alzheimer’s disease (TOAD): interim FDG PET analysis. Alzheimers Dement., 2018, 14(7), P1435-P1436.
[http://dx.doi.org/10.1016/j.jalz.2018.06.2411]


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VOLUME: 7
ISSUE: 1
Year: 2020
Published on: 06 September, 2020
Page: [11 - 23]
Pages: 13
DOI: 10.2174/2213235X07666191008103247

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