TOXI-SIM-A simulation tool for the analysis of mitochondrial and plasma membrane potentials

Heinrich J. Huber; Martin Plchut; Petronela Weisová; Heiko Düssmann; Jakub Wenus; Markus Rehm; Manus W. Ward; Jochen H.M. Prehn

doi:10.1016/j.jneumeth.2008.09.003

TOXI-SIM-A simulation tool for the analysis of mitochondrial and plasma membrane potentials

Heinrich J. Huber, Martin Plchut, Petronela Weisová, Heiko Düssmann, Jakub Wenus, Markus Rehm, Manus W. Ward, Jochen H.M. Prehn^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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 (Δψ_m) over time during glutamate excitotoxicity. However, fluorescently charged dyes such as TMRM respond to changes in both Δψ_m and the plasma membrane (Δψ_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 Δψ_m and Δψ_p over time. Based on Ca²⁺ 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).

Original language	English (US)
Pages (from-to)	270-275
Number of pages	6
Journal	Journal of neuroscience methods
Volume	176
Issue number	2
DOIs	https://doi.org/10.1016/j.jneumeth.2008.09.003
State	Published - Jan 30 2009
Externally published	Yes

Bibliographical note

Funding Information:
This research was supported by grants from Science Foundation Ireland (03/RP1/B344), the Irish Higher Education Authority (National Biophotonics and Imaging Platform Ireland, PRTLI Cycle 4) and the European Union (FP7, APO-SYS) to JHMP, by a grant from the Irish Health Research Board (HRB RP 181/2006) to MWW, and by Siemens Research Ireland.

Keywords

Bioenergetics
Excitotoxicity
Glutamate
Mathematical modelling
Mitochondrial membrane potential
Plasma membrane potential

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.jneumeth.2008.09.003

Cite this

@article{6c514ce01090470487262a231604366d,

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 (Δψm) over time during glutamate excitotoxicity. However, fluorescently charged dyes such as TMRM respond to changes in both Δψm and the plasma membrane (Δψp) 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 Δψm and Δψp over time. Based on Ca2+ 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).",

keywords = "Bioenergetics, Excitotoxicity, Glutamate, Mathematical modelling, Mitochondrial membrane potential, Plasma membrane potential",

author = "Huber, {Heinrich J.} and Martin Plchut and Petronela Weisov{\'a} and Heiko D{\"u}ssmann and Jakub Wenus and Markus Rehm and Ward, {Manus W.} and Prehn, {Jochen H.M.}",

note = "Funding Information: This research was supported by grants from Science Foundation Ireland (03/RP1/B344), the Irish Higher Education Authority (National Biophotonics and Imaging Platform Ireland, PRTLI Cycle 4) and the European Union (FP7, APO-SYS) to JHMP, by a grant from the Irish Health Research Board (HRB RP 181/2006) to MWW, and by Siemens Research Ireland.",

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doi = "10.1016/j.jneumeth.2008.09.003",

language = "English (US)",

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pages = "270--275",

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T1 - TOXI-SIM-A simulation tool for the analysis of mitochondrial and plasma membrane potentials

AU - Huber, Heinrich J.

AU - Plchut, Martin

AU - Weisová, Petronela

AU - Düssmann, Heiko

AU - Wenus, Jakub

AU - Rehm, Markus

AU - Ward, Manus W.

AU - Prehn, Jochen H.M.

N1 - Funding Information: This research was supported by grants from Science Foundation Ireland (03/RP1/B344), the Irish Higher Education Authority (National Biophotonics and Imaging Platform Ireland, PRTLI Cycle 4) and the European Union (FP7, APO-SYS) to JHMP, by a grant from the Irish Health Research Board (HRB RP 181/2006) to MWW, and by Siemens Research Ireland.

PY - 2009/1/30

Y1 - 2009/1/30

N2 - 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 (Δψm) over time during glutamate excitotoxicity. However, fluorescently charged dyes such as TMRM respond to changes in both Δψm and the plasma membrane (Δψp) 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 Δψm and Δψp over time. Based on Ca2+ 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).

AB - 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 (Δψm) over time during glutamate excitotoxicity. However, fluorescently charged dyes such as TMRM respond to changes in both Δψm and the plasma membrane (Δψp) 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 Δψm and Δψp over time. Based on Ca2+ 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).

KW - Bioenergetics

KW - Excitotoxicity

KW - Glutamate

KW - Mathematical modelling

KW - Mitochondrial membrane potential

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SN - 0165-0270

VL - 176

SP - 270

EP - 275

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JF - Journal of neuroscience methods

IS - 2

ER -

TOXI-SIM-A simulation tool for the analysis of mitochondrial and plasma membrane potentials

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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