title: TOXI-SIM-A simulation tool for the analysis of mitochondrial and plasma membrane potentials.
abstract: Changes in the electrochemical gradients across biological membranes are excellent indicators of pathophysiological processes, drug action, or drug toxicity. Our previous studies have utilized the potentiometric probe tetramethylrhodamine methyl ester (TMRM) to characterize changes in mitochondrial function by monitoring alterations in the mitochondrial membrane potential (Deltapsi(m)) over time during glutamate excitotoxicity. However, fluorescently charged dyes such as TMRM respond to changes in both Deltapsi(m) and the plasma membrane (Deltapsi(p)) potentials making whole cell fluorescence data difficult to interpret. Here we have implemented a mathematical model that exploits the Nernstian behaviour of TMRM and uses automated Newton based root-finding fitting (TOXI-SIM) to model changes in TMRM fluorescence from multiple cells simultaneously, providing output on changes in Deltapsi(m) and Deltapsi(p) over time. Based on Ca(2+) responses, TOXI-SIM allows for an accurate modelling of TMRM traces for different injury paradigms (necrosis, apoptosis, tolerance). TOXI-SIM is provided as a user friendly public web service for trace analysis, with an additional online data base provided for the storage and retrieval of experimental traces (http://systemsbiology.rcsi.ie/tmrm/index.html).
authors.affiliation: Systems and Computational Biology Group, RCSI Research Institute, Ireland.
authors.forename: Heinrich J
authors.initials: HJ
authors.lastname: Huber
authors.forename: Martin
authors.initials: M
authors.lastname: Plchut
authors.forename: Petronela
authors.initials: P
authors.lastname: Weisová
authors.forename: Heiko
authors.initials: H
authors.lastname: Düssmann
authors.forename: Jakub
authors.initials: J
authors.lastname: Wenus
authors.forename: Markus
authors.initials: M
authors.lastname: Rehm
authors.forename: Manus W
authors.initials: MW
authors.lastname: Ward
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D015233:Models, Statistical; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure*; D051381:Rats; D012235:Rhodamines / Q000378:metabolism; D013997:Time Factors
chemical_list: D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D012235:Rhodamines; C401833:tetramethylrhodamine methyl ester; D016291:Dizocilpine Maleate; D002118:Calcium