Poster for ISB Symposium 2014

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Cancer-related perturbation (DJ1 up-regulation) makes the model more resistant to elevated ROS generation. PD-related perturbations increase ROS concentration and the fraction of damaged mitochondria, and cause the greatest decrease to the number of healthy mitochondria. A kinetic model of ROS management and its instantiation for cancer, Parkinson’s disease and Huntington’s disease By integrating information from network analysis, epidemiological data and experimental evidences we have parameterized the model for cancer, PD and HD: Alexey Kolodkin 1,2 , Vineet Sangar 2 , Evangelos Simeonidis 1,2 , Andrew Ignatenko 3 , Kuyong Kim 4 , Nathan Brady 4 , and Rudi Balling 1 1 Luxembourg Centre for Systems Biomedicine (LCSB), Luxembourg | 2 Institute for Systems Biology, Seattle, USA | 3 Faculty of Science, Technology and Communication, University of Luxembourg, Luxembourg, Luxembourg | 4 German Cancer Research Center, Heidelberg, Germany Model instantiations for cancer, PD and HD Model 5 Combines the design principles of model 3 with detailed resolution of model 4. In vivo evidence demonstrates three fundamental interconnected adaptive survival mechanisms , which protect against excessive ROS generated during mitochondrial dysfunction: (i) autophagy/mitophagy, (ii) adaptive antioxidant response and (iii) NFkB signaling in cancer and neurodegeneration. We have constructed and have been expanding a kinetic model, which recapitulates the consensus understanding of the mechanisms responsible for the cellular ROS-management system. Using this model, we have performed modular analysis to study emergent behaviors. Starting with the simplest model, we have stepwise added new modules. Our analysis has allowed us to identify the qualitative role (emergent behavior) attributed to each module and thus attempt to understand the design principles of the system. We propose a detailed, mechanistic, kinetic model for studying how mutations relevant for diseases such as Parkinson’s disease (PD) and cancer affect the emergent behavior of the ROS management network. Introduction The influence of excessive ROS generation on mitochondrial state and ROS levels: Model 4 Added detailed description of NRF2- KEAP1 and alfa- synuclein, Electron Transport Chain; DJ1, Parkin, Pink1 and space aspect (nucleus) to simulate PD and cancer related pathophysiol ogy. Model 1 Aging of mitochondria from Mitoch 1 (Healthy) to Mitoch 2 (Damaged). Mitoch 2 produces ROS. ROS activates aging (damaging) of Mitoch 1 to Mitoch 2. Antioxidant response (green) and mitophagy (blue). Model 2 The nrf2-keap1 system was added (regulation of p62 and antioxidants concentration) (brown). Model 3 NFkB signalling added (regulation of “recovery” of mitochondria) (violet). Homeostasis: ROS and healthy mitochondria return (almost) back to normal upon step- wise increase of ROS generation. But the system is unstable. Homeostasis works even better and stability is improved. The influence of PD-related increase of alfa- synuclein concentration on mitochondrial state and ROS levels: mitochondria and ROS module antioxidant response mitophagy keap1-nrf2 module DJ-1 uncoupling proteins NFkB module alfa- synucleins Design principles of ROS management Gradual increase of ROS synthesis results in gradual increase of ROS concentration (no homeostasis): ROS ROS ROS ROS production per mitochondrion (ROS/(Mitoch total) when all parameters are randomly perturbed: Model 1 Model 2 Model 3 Healthy/Damaged mitochondria Fraction of Healthy-to-Damaged mitochondria when all parameters are randomly perturbed: Model 3 performs better than models 2 and 1 Follow on twitter: Link to poster:

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A kinetic model of ROS management and its instantiation for cancer, Parkinson’s disease and Huntington’s disease

Transcript of Poster for ISB Symposium 2014

Page 1: Poster for ISB Symposium 2014

• Cancer-related perturbation (DJ1 up-regulation) makes the model more resistant to elevated ROS generation.

• PD-related perturbations increase ROS concentration and the fraction of damaged mitochondria, and cause the greatest decrease to the number of healthy mitochondria.

A kinetic model of ROS management and its instantiation for cancer, Parkinson’s disease and Huntington’s disease

By integrating information from network analysis, epidemiological data and experimental evidences we have parameterized the model for cancer, PD and HD:

Alexey Kolodkin1,2, Vineet Sangar2, Evangelos Simeonidis1,2, Andrew Ignatenko3, Kuyong Kim4, Nathan Brady4, and Rudi Balling1

1Luxembourg Centre for Systems Biomedicine (LCSB), Luxembourg | 2Institute for Systems Biology, Seattle, USA |3Faculty of Science, Technology and Communication, University of Luxembourg, Luxembourg, Luxembourg | 4German Cancer Research Center, Heidelberg, Germany

Model instantiations for cancer, PD and HDModel 5Combines the design principles of model 3 with detailed resolution of model 4.

In vivo evidence demonstrates three fundamental interconnected adaptive survival mechanisms , which protect against excessive ROS generated during mitochondrial dysfunction: (i) autophagy/mitophagy, (ii) adaptive antioxidant response and (iii) NFkB signaling in cancer and neurodegeneration.We have constructed and have been expanding a kinetic model, which recapitulates the consensus understanding of the mechanisms responsible for the cellular ROS-management system. Using this model,

we have performed modular analysis to study emergent behaviors. Starting with the simplest model, we have stepwise added new modules. Our analysis has allowed us to identify the qualitative role (emergent behavior) attributed to each module and thus attempt to understand the design principles of the system.We propose a detailed, mechanistic, kinetic model for studying how mutations relevant for diseases such as Parkinson’s disease (PD) and cancer affect the emergent behavior of the ROS management network.

Introduction

The influence of excessive ROS generation on mitochondrial state and ROS levels:

Model 4 Added detailed description of NRF2-KEAP1 and alfa-synuclein,Electron Transport Chain; DJ1, Parkin, Pink1 and space aspect (nucleus) to simulate PD and cancer related pathophysiology.

Model 1Aging of mitochondria from Mitoch 1 (Healthy) to Mitoch 2 (Damaged). Mitoch 2 produces ROS. ROS activates aging (damaging) of Mitoch 1 to Mitoch 2. Antioxidant response (green) and mitophagy (blue).

Model 2 The nrf2-keap1 system was added (regulation of p62 and antioxidants concentration) (brown).

Model 3 NFkB signalling added (regulation of “recovery” of mitochondria)(violet).

Homeostasis: ROS and healthy mitochondria return (almost) back to normal upon step-wise increase of ROS generation. But the system is unstable.

Homeostasis works even better and stability is improved.

The influence of PD-related increase of alfa-synuclein concentration on mitochondrial state and ROS levels:

mitochondria and ROS module

antioxidant response mitophagy

keap1-nrf2 module

DJ-1

uncoupling proteins

NFkB module

alfa-synucleins

Design principles of ROS management

Gradual increase of ROS synthesis results in gradual increase of ROS concentration (no homeostasis):

ROS

ROS

ROS

ROS production per mitochondrion (ROS/(Mitoch total) when all parameters are randomly perturbed:

Model 1 Model 2 Model 3

Hea

lthy/

Dam

aged

mito

chon

dria

Fraction of Healthy-to-Damaged mitochondria when all parameters are randomly perturbed:

Model 3 performs better than models 2 and 1

Follow on twitter: Link to poster: