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1.  A Systems Biology Approach Identifies Molecular Networks Defining Skeletal Muscle Abnormalities in Chronic Obstructive Pulmonary Disease 
PLoS Computational Biology  2011;7(9):e1002129.
Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation. Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy. Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate. In this study, we have applied a network biology approach to model the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators. Our model shows that failure to co-ordinately activate expression of several tissue remodelling and bioenergetics pathways is a specific landmark of COPD diseased muscles. Our findings also suggest that this phenomenon may be linked to an abnormal expression of a number of histone modifiers, which we discovered correlate with oxygen utilization. These observations raised the interesting possibility that cell hypoxia may be a key factor driving skeletal muscle degeneration in COPD patients.
Author Summary
Chronic Obstructive Pulmonary Disease (COPD) is a major life threatening disease of the lungs, characterized by airflow limitation and chronic inflammation. Progressive reduction of the body muscle mass is a condition linked to COPD that significantly decreases quality of life and survival. Physical exercise has been proposed as a therapeutic option but its utility is still a matter of debate. The mechanisms underlying muscle wasting are also still largely unknown. The results presented in this paper show that diseased muscles are largely unable to coordinate the expression of muscle remodelling and bioenergetics pathways and that the cause of this phenomena may be tissue hypoxia. These findings contrast with current hypotheses based on the role of chronic inflammation and show that a mechanism based on an oxygen driven, epigenetic control of these two important functions may be an important disease mechanism.
doi:10.1371/journal.pcbi.1002129
PMCID: PMC3164707  PMID: 21909251
2.  Reactive Oxygen Species Production by Forward and Reverse Electron Fluxes in the Mitochondrial Respiratory Chain 
PLoS Computational Biology  2011;7(3):e1001115.
Reactive oxygen species (ROS) produced in the mitochondrial respiratory chain (RC) are primary signals that modulate cellular adaptation to environment, and are also destructive factors that damage cells under the conditions of hypoxia/reoxygenation relevant for various systemic diseases or transplantation. The important role of ROS in cell survival requires detailed investigation of mechanism and determinants of ROS production. To perform such an investigation we extended our rule-based model of complex III in order to account for electron transport in the whole RC coupled to proton translocation, transmembrane electrochemical potential generation, TCA cycle reactions, and substrate transport to mitochondria. It fits respiratory electron fluxes measured in rat brain mitochondria fueled by succinate or pyruvate and malate, and the dynamics of NAD+ reduction by reverse electron transport from succinate through complex I. The fitting of measured characteristics gave an insight into the mechanism of underlying processes governing the formation of free radicals that can transfer an unpaired electron to oxygen-producing superoxide and thus can initiate the generation of ROS. Our analysis revealed an association of ROS production with levels of specific radicals of individual electron transporters and their combinations in species of complexes I and III. It was found that the phenomenon of bistability, revealed previously as a property of complex III, remains valid for the whole RC. The conditions for switching to a state with a high content of free radicals in complex III were predicted based on theoretical analysis and were confirmed experimentally. These findings provide a new insight into the mechanisms of ROS production in RC.
Author Summary
Respiration at the level of mitochondria is considered as delivery of electrons and protons from NADH or succinate to oxygen through a set of transporters constituting the respiratory chain (RC). Mitochondrial respiration, dealing with transfer of unpaired electrons, may produce reactive oxygen species (ROS) such as O2− and subsequently H2O2 as side products. ROS are chemically very active and can cause oxidative damage to cellular components. The production of ROS, normally low, can increase under stress to the levels incompatible with cell survival; thus, understanding the ways of ROS production in the RC represents a vital task in research. We used mathematical modeling to analyze experiments with isolated brain mitochondria aimed to study relations between electron transport and ROS production. Elsewhere we reported that mitochondrial complex III can operate in two distinct steady states at the same microenvironmental conditions, producing either low or high levels of ROS. Here, this property of bistability was confirmed for the whole RC. The associations between measured ROS production and computed individual free radical levels in complexes I and III were established. The discovered phenomenon of bistability is important as a basis for new strategies in organ transplantation and therapy.
doi:10.1371/journal.pcbi.1001115
PMCID: PMC3068929  PMID: 21483483
3.  Bistability of Mitochondrial Respiration Underlies Paradoxical Reactive Oxygen Species Generation Induced by Anoxia 
PLoS Computational Biology  2009;5(12):e1000619.
Increased production of reactive oxygen species (ROS) in mitochondria underlies major systemic diseases, and this clinical problem stimulates a great scientific interest in the mechanism of ROS generation. However, the mechanism of hypoxia-induced change in ROS production is not fully understood. To mathematically analyze this mechanism in details, taking into consideration all the possible redox states formed in the process of electron transport, even for respiratory complex III, a system of hundreds of differential equations must be constructed. Aimed to facilitate such tasks, we developed a new methodology of modeling, which resides in the automated construction of large sets of differential equations. The detailed modeling of electron transport in mitochondria allowed for the identification of two steady state modes of operation (bistability) of respiratory complex III at the same microenvironmental conditions. Various perturbations could induce the transition of respiratory chain from one steady state to another. While normally complex III is in a low ROS producing mode, temporal anoxia could switch it to a high ROS producing state, which persists after the return to normal oxygen supply. This prediction, which we qualitatively validated experimentally, explains the mechanism of anoxia-induced cell damage. Recognition of bistability of complex III operation may enable novel therapeutic strategies for oxidative stress and our method of modeling could be widely used in systems biology studies.
Author Summary
The levels of reactive oxygen species (ROS) that are generated as a side product of mitochondrial respiratory electron transport largely define the extent of oxidative stress in living cells. Free radicals formed in electron transport, such as ubisemiquinone, could pass their non-paired electron directly to oxygen, thus producing superoxide radical that gives rise to a variety of ROS. It is well known in clinical practice that upon recommencing oxygen supply after anoxia a tissue produces much more ROS than before the anoxia, and the state of high ROS production is stable. The mechanism of switching from low to high ROS production by temporal anoxia was unknown, in part because of the lack of detailed mathematical description of hundreds of redox states of respiratory complexes, which are formed in the process of electron transport. A new methodology of automated construction of large systems of differential equations allowed us to describe the system in detail and predicts that the mechanism of paradoxical effect of anoxia-reoxygenation could be defined by the properties of complex III of mitochondrial respiratory chain. Our experiments confirmed that the effect of hypoxia-reoxygenation is confined by intramitochondrial processes since it is observed in isolated mitochondria.
doi:10.1371/journal.pcbi.1000619
PMCID: PMC2789320  PMID: 20041200

Results 1-3 (3)