Reference : Detection and characterization of critical transitions in mitochondrial activity via ...
Dissertations and theses : Doctoral thesis
Life sciences : Multidisciplinary, general & others
http://hdl.handle.net/10993/17706
Detection and characterization of critical transitions in mitochondrial activity via high content screening
English
Trefois, Christophe mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
11-Aug-2014
University of Luxembourg, ​Luxembourg, ​​Luxembourg
Docteur en Biologie
284
Balling, Rudi mailto
Sauter, Thomas mailto
Bouvry, Pascal mailto
Gunzer, Matthias mailto
Walter, Thomas mailto
[en] High-content imaging ; Critical transitions ; Tipping points ; Criticality ; Alternative Stable States ; HeLa ; Microscopy ; High-content screening ; HCS ; Parkinson's disease
[en] Critical transitions exist in many dynamical systems, ranging from the Earth’s cli-
mate system to microcosm populations. During a critical transition, the state of
a dynamical system abruptly changes from one stable state to another, typically
without obvious prior warning. Preventing such abrupt changes remains a chal-
lenge, however recently, several metrics were suggested as early warning signals.
These indicators are thought to have predictive value for upcoming critical transi-
tions. In Parkinson’s disease, there are no detectable motor symptoms in a patient
until neuronal dopaminergic cell death exceeds 60–70%. Being able to define early
warning signals in a disease context could open new avenues for both preventive and
disease modifying treatments. We hypothesize that the dynamics of progression of
some disorders including Parkinson’s disease could be manifested by critical tran-
sitions. However, before rushing into medical applications, a thorough framework
needs to be developed that aims to describe such nonlinear dynamics in cellular
systems. In this thesis, we set out to study critical transitions in a simple cellular
model using mitochondrial membrane potential ∆Ψ m as readout. To identify criti-
cal transitions, we established a modular high-content screening platform allowing
systematic perturbation of oxidative phosphorylation. To increase the probability
for detecting a critical transition in ∆Ψ m , five inhibitory compounds were combined
in multiple pairwise concentration landscapes. We show that critical transitions, de-
tectable via ∆Ψ m , are an intrinsic property of the cellular system studied and that
two-component Gaussian mixture models adequately capture the dynamics of the
critical transition occurring for the combination of Oligomycin A and Antimycin A.
Adding to that, we identified the coefficient of variation as a strong early warning
signal for the upcoming of the critical transitions. This thesis should serve as a
foundation for a broader application of critical transitions and early warning sig-
nals in both cell culture systems and translational studies aiming to understand the
nonlinear dynamics of biological systems.
Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) ; University of Luxembourg: High Performance Computing - ULHPC
Fonds National de la Recherche - FnR
Researchers ; Students ; General public
http://hdl.handle.net/10993/17706
This work is published under CC BY-NC-ND

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