ROS-management in Parkinson’s disease: Dynamic blue-print domino-based model and design principles study. Dynamic modelling of ROS management and ROS-induced mitophagy

Poster (2014, October)

Dynamic modelling of ROS management and ROS-induced mitophagy

Poster (2014, June)

Modeling cellular ROS defense in mitochondrial-related diseases

Poster (2013, July 22)

Reactive Oxygen Species (ROS) generation is an unavoidable background process during normal cellular function. The main contributor to ROS production is the electron transport chain, which reduces oxygen ... [more ▼]

Reactive Oxygen Species (ROS) generation is an unavoidable background process during normal cellular function. The main contributor to ROS production is the electron transport chain, which reduces oxygen to water. Some incompletely-reduced oxygen species escape and oxidize a variety of organic molecules, leading to molecular dysfunction and initiating a positive feedback loop of ever increasing active radical production. The increased concentration of ROS damages the mitochondria, therefore further elevating the rate of ROS generation. Healthy cells manage ROS enzymatically and by mitophagy of damaged mitochondria. The precise tuning of the latter mechanism is crucial for cell survival and is controlled by a ROS-induced regulatory network. We have built a set of kinetic models of varying complexity, based on the current understanding of the mechanism of cellular ROS defense. Our models allow simulation of various patho-physiological scenarios related to mitochondrial dysfunction and the failure of the system of ROS regulation in human cells. We employ the models we have constructed to simulate the effects of diseases related to mitochondrial dysfunction and excessive ROS generation, such as Parkinson’s disease, Huntington’s disease and cancer. Experimental evidence is used for model fitting, and we propose model improvements based on incorporation of single-cell experimental measurements. Finally, we discuss the perspective of integrating our kinetic models with genome-scale, constraint-based, tissue-specific models of metabolism, in order to study the effect of ROS misregulation on metabolic phenotype. [less ▲]

Mechanistic modeling of aberrant energy metabolism in human disease.

in Frontiers in Physiology (2012), 3

Dysfunction in energy metabolism-including in pathways localized to the mitochondria-has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases ... [more ▼]

Dysfunction in energy metabolism-including in pathways localized to the mitochondria-has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases to type II diabetes. The inherent complexities of energy and mitochondrial metabolism present a significant obstacle in the effort to understand the role that these molecular processes play in the development of disease. To help unravel these complexities, systems biology methods have been applied to develop an array of computational metabolic models, ranging from mitochondria-specific processes to genome-scale cellular networks. These constraint-based (CB) models can efficiently simulate aspects of normal and aberrant metabolism in various genetic and environmental conditions. Development of these models leverages-and also provides a powerful means to integrate and interpret-information from a wide range of sources including genomics, proteomics, metabolomics, and enzyme kinetics. Here, we review a variety of mechanistic modeling studies that explore metabolic functions, deficiency disorders, and aberrant biochemical pathways in mitochondria and related regions in the cell. [less ▲]