Candidate Metabolic Network States in Human Mitochondria Export

@article{citeulike:1065541, abstract = {10.1074/jbc.M409072200 The human mitochondrial metabolic network was recently reconstructed based on proteomic and biochemical data. Linear programming and uniform random sampling were applied herein to identify candidate steady states of the metabolic network that were consistent with the imposed physico-chemical constraints and available experimental data. The activity of the mitochondrion was studied under four metabolic conditions: normal physiologic, diabetic, ischemic, and dietetic. Pairwise correlations between steady-state reaction fluxes were calculated in each condition to evaluate the dependence among the reactions in the network. Applying constraints on exchange fluxes resulted in predictions for intracellular fluxes that agreed with experimental data. Analyses of the steady-state flux distributions showed that the experimentally observed reduced activity of pyruvate dehydrogenase could be a result of stoichiometric constraints and therefore would not necessarily require enzymatic inhibition. The observed changes in the energy metabolism of the mitochondrion under diabetic conditions were used to evaluate the impact of previously suggested treatments. The results showed that neither normalized glucose uptake nor decreased ketone body uptake have a positive effect on the mitochondrial energy metabolism or network flexibility. Taken together, this study showed that sampling of the steady-state flux space is a powerful method to investigate network properties under different conditions and provides a basis for evaluations of effects of potential disease treatments.}, address = {Department of Bioengineering, University of California, San Diego, California 92093-0412, USA.}, author = {Thiele, Ines and Price, Nathan D. and Vo, Thuy D. and Palsson, Bernhard}, booktitle = {Journal of Biological Chemistry}, citeulike-article-id = {1065541}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M409072200}, citeulike-linkout-1 = {http://www.jbc.org/content/280/12/11683.abstract}, citeulike-linkout-2 = {http://www.jbc.org/content/280/12/11683.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/15572364}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=15572364}, day = {25}, doi = {10.1074/jbc.M409072200}, issn = {0021-9258}, journal = {J Biol Chem}, keywords = {disease, flux, human, metabolic, mitochondria, model, network}, month = {March}, number = {12}, pages = {11683--11695}, posted-at = {2007-01-24 17:00:01}, priority = {5}, title = {Candidate Metabolic Network States in Human Mitochondria}, url = {http://dx.doi.org/10.1074/jbc.M409072200}, volume = {280}, year = {2005} }

TY - JOUR ID - citeulike:1065541 L3 - citeulike-article-id:1065541 N2 - 10.1074/jbc.M409072200 The human mitochondrial metabolic network was recently reconstructed based on proteomic and biochemical data. Linear programming and uniform random sampling were applied herein to identify candidate steady states of the metabolic network that were consistent with the imposed physico-chemical constraints and available experimental data. The activity of the mitochondrion was studied under four metabolic conditions: normal physiologic, diabetic, ischemic, and dietetic. Pairwise correlations between steady-state reaction fluxes were calculated in each condition to evaluate the dependence among the reactions in the network. Applying constraints on exchange fluxes resulted in predictions for intracellular fluxes that agreed with experimental data. Analyses of the steady-state flux distributions showed that the experimentally observed reduced activity of pyruvate dehydrogenase could be a result of stoichiometric constraints and therefore would not necessarily require enzymatic inhibition. The observed changes in the energy metabolism of the mitochondrion under diabetic conditions were used to evaluate the impact of previously suggested treatments. The results showed that neither normalized glucose uptake nor decreased ketone body uptake have a positive effect on the mitochondrial energy metabolism or network flexibility. Taken together, this study showed that sampling of the steady-state flux space is a powerful method to investigate network properties under different conditions and provides a basis for evaluations of effects of potential disease treatments. IS - 12 JF - J Biol Chem SN - 0021-9258 AD - Department of Bioengineering, University of California, San Diego, California 92093-0412, USA. EP - 11695 TI - Candidate Metabolic Network States in Human Mitochondria VL - 280 T2 - Journal of Biological Chemistry SP - 11683 KW - disease KW - flux KW - human KW - metabolic KW - mitochondria KW - model KW - network AU - Thiele, Ines AU - Price, Nathan AU - Vo, Thuy AU - Palsson, Bernhard PY - 2005/03/25/ UR - http://dx.doi.org/10.1074/jbc.M409072200 ER -