Multi-Target Analysis and Design of Mitochondrial Metabolism

Angione, Claudio; Costanza, Jole; Carapezza, Giovanni; LiĆ³, Pietro; Nicosia, Giuseppe
September 2015
PLoS ONE;9/16/2015, Vol. 10 Issue 9, p1
Academic Journal
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.


Related Articles

  • Inhibition of poly(ADP-ribose) polymerase (PARP) influences the mode of sulfur mustard (SM)-induced cell death in HaCaT cells. Kehe, K.; Raithel, K.; Kreppel, H.; Jochum, M.; Worek, F.; Thiermann, H. // Archives of Toxicology;Jul2008, Vol. 82 Issue 7, p461 

    Sulfur mustard (SM) is a bifunctional alkylating agent. Its primary toxic consequence is severe skin damage with blisters, occurring after skin contact. These vesicant properties of SM have been linked to cell death of proliferating keratinocytes in the basal layer of the skin. Catalytic...

  • Naturally fluorescent molecules may serve as cancer biomarker. PEDERSEN, AMANDA // Diagnostics & Imaging Week;4/16/2009, Vol. 12 Issue 15, p1 

    The article reports that excess amounts of a naturally fluorescent molecule, nicotinamide adenine dinucleotide (NADH), might serve as a natural biomarker for cancer. According to researchers from Pennsylvania State University at University Park, the molecule could be the key to differentiating...

  • The Importance of NAD in Multiple Sclerosis. Penberthy, W. Todd; Tsunoda, Ikuo // Current Pharmaceutical Design;1/1/2009, Vol. 15 Issue 1, p64 

    The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory demyelinating disease in the central nervous system (CNS). During chronic CNS inflammation, nicotinamide adenine dinucleotide (NAD) concentrations are altered by (T helper) Th1-derived cytokines through...

  • Malate-aspartate shuttle mediates the intracellular ATP levels, antioxidation capacity and survival of differentiated PC12 cells. Caixia Wang; Heyu Chen; Jie Zhang; Yunyi Hong; Xianting Ding; Weihai Ying // International Journal of Physiology, Pathophysiology & Pharmacol;2014, Vol. 6 Issue 2, p109 

    NAD+ and NADH play pivotal roles in numerous redox reactions in cells. While increasing evidence has indicated important roles of NAD+ in cell survival and cellular functions, there has been distinct deficiency in the studies regarding the biological functions of NADH. NADH shuttles mediate the...

  • Mitochondria-localized NAD biosynthesis by nicotinamide mononucleotide adenylyltransferase in Jerusalem artichoke ( Helianthus tuberosus L.) heterotrophic tissues. Di Martino, Catello; Pallotta, Maria // Planta;Oct2011, Vol. 234 Issue 4, p657 

    Current studies in plants suggest that the content of the coenzyme NAD is variable and potentially important in determining cell fate. In cases that implicate NAD consumption, re-synthesis must occur to maintain dinucleotide pools. Despite information on the pathways involved in NAD synthesis in...

  • Influence of Altered NADH Metabolic Pathway on the Respiratory-deficient Mutant of Rhizopus oryzae and its L-lactate Production. Shu, Chang; Guo, Chenchen; Luo, Shuizhong; Jiang, Shaotong; Zheng, Zhi // Applied Biochemistry & Biotechnology;Aug2015, Vol. 176 Issue 7, p2053 

    Respiratory-deficient mutants of Rhizopus oryzae ( R. oryzae) AS 3.3461 were acquired by ultraviolet (UV) irradiation to investigate changes in intracellular NADH metabolic pathway and its influence on the fermentation characteristics of the strain. Compared with R. oryzae AS 3.3461, the...

  • Review: can diet influence the selective advantage of mitochondrial DNA haplotypes? Ballard, J. William O.; Youngson, Neil A. // Bioscience Reports;Dec2015, Vol. 35 Issue 6, p1 

    This review explores the potential for changes in dietary macronutrients to differentially influence mitochondrial bioenergetics and thereby the frequency of mtDNA haplotypes in natural populations. Such dietary modification may be seasonal or result from biogeographic or demographic shifts....

  • Nicotinamide Pretreatment Protects Cardiomyocytes against Hypoxia-Induced Cell Death by Improving Mitochondrial Stress. Tong, Da-Li; Zhang, Dong-Xia; Xiang, Fei; Teng, Miao; Jiang, Xu-Pin; Hou, Jing-Ming; Zhang, Qiong; Huang, Yue-Sheng // Pharmacology;Aug2012, Vol. 90 Issue 1/2, p11 

    Background/Aims: Nicotinamide plays a protective role in hypoxia-induced cardiomyocyte dysfunction. However, the underlying molecular mechanisms remain poorly understood. The purpose of this study was to investigate these and the effect of nicotinamide pretreatment on hypoxic cardiomyocytes....

  • Genealogy of an ancient protein family: the Sirtuins, a family of disordered members. Costantini, Susan; Sharma, Ankush; Raucci, Raffaele; Costantini, Maria; Autiero, Ida; Colonna, Giovanni // BMC Evolutionary Biology;2013, Vol. 13 Issue 1, p1 

    Sirtuins genes are widely distributed by evolution and have been found in eubacteria, archaea and eukaryotes. While prokaryotic and archeal species usually have one or two sirtuin homologs, in humans as well as in eukaryotes we found multiple versions and in mammals this family is comprised of...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics