title: Multi-Target Analysis and Design of Mitochondrial Metabolism.
abstract: Analyzing and optimizing biological models is often identified as a research priority in biomedical engineering. An important feature of a model should be the ability to find the best condition in which an organism has to be grown in order to reach specific optimal output values chosen by the researcher. In this work, we take into account a mitochondrial model analyzed with flux-balance analysis. The optimal design and assessment of these models is achieved through single- and/or multi-objective optimization techniques driven by epsilon-dominance and identifiability analysis. Our optimization algorithm searches for the values of the flux rates that optimize multiple cellular functions simultaneously. The optimization of the fluxes of the metabolic network includes not only input fluxes, but also internal fluxes. A faster convergence process with robust candidate solutions is permitted by a relaxed Pareto dominance, regulating the granularity of the approximation of the desired Pareto front. We find that the maximum ATP production is linked to a total consumption of NADH, and reaching the maximum amount of NADH leads to an increasing request of NADH from the external environment. Furthermore, the identifiability analysis characterizes the type and the stage of three monogenic diseases. Finally, we propose a new methodology to extend any constraint-based model using protein abundances.
authors.affiliation: Computer Laboratory-University of Cambridge, Cambridge, United Kingdom.
authors.forename: Claudio
authors.initials: C
authors.lastname: Angione
authors.affiliation: Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Jole
authors.initials: J
authors.lastname: Costanza
authors.affiliation: Department of Mathematics and Computer Science-University of Catania, Catania, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Carapezza
authors.affiliation: Computer Laboratory-University of Cambridge, Cambridge, United Kingdom.
authors.forename: Pietro
authors.initials: P
authors.lastname: Lió
authors.affiliation: Department of Mathematics and Computer Science-University of Catania, Catania, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nicosia
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000465:Algorithms; D007655:Ketoglutarate Dehydrogenase Complex / Q000172:deficiency; D064688:Metabolic Flux Analysis; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D009243:NAD / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics
chemical_list: D024101:Mitochondrial Proteins; D009243:NAD; D000255:Adenosine Triphosphate; D007655:Ketoglutarate Dehydrogenase Complex; D013385:Succinate Dehydrogenase