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See detailGenome-Scale Methods Converge on Key Mitochondrial Genes for the Survival of Human Cardiomyocytes in Hypoxia
Edwards, Lindsay; Sigurdsson, Martin I; Robbins, Peter A et al

in Circulation: Cardiovascular Genetics (2014)

Background—Any reduction in myocardial oxygen delivery relative to its demands can impair cardiac contractile performance. Understanding the mitochondrial metabolic response to hypoxia is key to ... [more ▼]

Background—Any reduction in myocardial oxygen delivery relative to its demands can impair cardiac contractile performance. Understanding the mitochondrial metabolic response to hypoxia is key to understanding ischemia tolerance in the myocardium. We employed a novel combination of two genome-scale methods to study key processes underlying human myocardial hypoxia tolerance. In particular, we hypothesised that computational modelling and evolution would identify similar genes as critical to human myocardial hypoxia tolerance. Methods and Results—We analysed a reconstruction of the cardiac mitochondrial metabolic network using constraint-based methods, under conditions of simulated hypoxia. We used flux balance analysis, random sampling and principle components analysis to explore feasible steady-state solutions. Hypoxia blunted maximal ATP (-17%) and haeme (-75%) synthesis and shrank the feasible solution space. TCA and urea cycle fluxes were also reduced in hypoxia, but phospholipid synthesis was increased. Using mathematical optimization methods, we identified reactions that would be critical to hypoxia tolerance in the human heart. We used data regarding SNP frequency and distribution in the genomes of Tibetans (whose ancestors have resided in persistent high-altitude hypoxia for several millennia). Six reactions were identified by both methods as being critical to mitochondrial ATP production in hypoxia: phosphofructokinase, phosphoglucokinase, Complex II, Complex IV, aconitase and fumarase. Conclusions—Mathematical optimization and evolution converged on similar genes as critical to human myocardial hypoxia tolerance. Our approach is unique and completely novel and demonstrates that genome-scale modelling and genomics can be used in tandem to provide new insights into cardiovascular genetics. [less ▲]

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See detailApplying systems biology methods to the study of human physiology in extreme environments
Edwards, Lindsay; Thiele, Ines UL

in Extreme Physiology & Medicine (2013), 2(8),

Systems biology is defined in this review as ‘an iterative process of computational model building and experimental model revision with the aim of understanding or simulating complex biological systems’ ... [more ▼]

Systems biology is defined in this review as ‘an iterative process of computational model building and experimental model revision with the aim of understanding or simulating complex biological systems’. We propose that, in practice, systems biology rests on three pillars: computation, the omics disciplines and repeated experimental perturbation of the system of interest. The number of ethical and physiologically relevant perturbations that can be used in experiments on healthy humans is extremely limited and principally comprises exercise, nutrition, infusions (e.g. Intralipid), some drugs and altered environment. Thus, we argue that systems biology and environmental physiology are natural symbionts for those interested in a system-level understanding of human biology. However, despite excellent progress in high-altitude genetics and several proteomics studies, systems biology research into human adaptation to extreme environments is in its infancy. A brief description and overview of systems biology in its current guise is given, followed by a mini review of computational methods used for modelling biological systems. Special attention is given to high-altitude research, metabolic network reconstruction and constraint-based modelling. [less ▲]

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