Reference : A kinetic model and design principles study of cellular ROS defence and its failure i...
Scientific congresses, symposiums and conference proceedings : Poster
Life sciences : Multidisciplinary, general & others
http://hdl.handle.net/10993/2988
A kinetic model and design principles study of cellular ROS defence and its failure in Parkinson’s disease
English
Kolodkin, Alexey mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Simeonidis, Vangelis mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Brady, Nathan [German Cancer Research Center, Heidelberg, Germany]
Balling, Rudi mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Aug-2012
36x56in
Yes
No
International
ICSB 2013 - 13th International Conference on Systems Biology
19-23 August 2013
University of Toronto
Toronto
Canada
[en] Mitochondrial generation of reactive oxygen species (ROS) is an unavoidable side effect of oxidative phosphorylation. To counteract the production of ROS, the cell employs two main strategies. The first one is to increase the consumption of ROS; this mechanism involves the superoxide dismutase enzyme and various antioxidants. The second strategy is to reduce the production of ROS by decreasing mitochondrial membrane potential and by increasing mitophagy. The precise tuning of the latter is crucial for cell survival: if mitophagy is too active, all mitochondria are lost and the cell suffers from reduced ATP capacity; if mitophagy is not active enough, dysfunctional mitochondria accumulate, more ROS is produced, and the cell undergoes unwanted programmed cell death. We hypothesize that a ROS-activated regulatory network is employed to coordinate the regulation of the rate of mitophagy, the expression of uncoupling proteins and the production of antioxidants, including SOD. In Parkinson’s disease (PD), the activities of several components of this regulatory network (e.g. KEAP1, PARK7, VDAC1, SQSTM1) are altered. This makes the cell susceptible to ROS damage. In the case of dopaminergic neurons, this effect can be particularly severe, because an additional pool of non-mitochondrial ROS generated during ROS-induced degradation of dopamine. In order to understand the functioning of the ROS-activated regulatory network in normal function and disease, we have built a kinetic model.

Our model includes 39 species and 45 reactions, with 56 kinetic parameters, either fitted or obtained from literature. Our model allows the simulation of PD-related ROS generation and mitochondrial damage and the identification of the design principles underlying the functioning of the network; for example, showing and explaining the synergy between the down-regulation of both VDAC1 and PARK7 occurring during PD. The kinetic model has great potential use for better understanding of the pathophysiology of PD and for the suggestion of novel mitochondria-related PD treatments.
Researchers
http://hdl.handle.net/10993/2988
www.icsb2012toronto.com

File(s) associated to this reference

Fulltext file(s):

FileCommentaryVersionSizeAccess
Open access
Kolodkin et al - ICSB2012.pdfConference posterAuthor postprint539.2 kBView/Open

Bookmark and Share SFX Query

All documents in ORBilu are protected by a user license.