PMID: 29889855 PMCID: PMC5995348 DOI: 10.1371/journal.pone.0197921 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995348/
The isolated mitochondria model consists of three regions (Buffer, mitochondria matrix and inter-membrane space). Major reactions include TCA cycle reactions and electron transport chain reactions. Transports exist between mitochondria matrix region and inter-membrane region. Most of the metabolites are assumed free permeable to mitochondria outer-membrane. The major biochemical species included in this model are: PYR: pyruvate, COA: coenzyme-A. ACOA: acetyl-COA, OXA: oxaloacetate, CIT: citrate, AKG: a-ketogluterate, SCOA: succinyl-COA, SUC: succinate, FUM: fumarate, MAL: malate, GLU: glutamate, ASP: aspartate, NAD and NADH: oxidized and reduced form of nicotinamide adenine dinucleotide, FAD and FADH2: oxidized and reduced form of Flavin adenine dinucleotide, ADP and ATP: adenosine triphosphate and adenosine diphosphate, UQ and UQH2: oxidized and reduced form of ubiquinone. C(oxi) and C(red): oxidized and reduced form of cytochrome c.
Integrated computational modeling provides a mechanistic and quantitative framework for describing lung mitochondrial bioenergetics. Thus, the objective of this study was to develop and validate a thermodynamically-constrained integrated computational model of the bioenergetics of isolated lung mitochondria. The model incorporates the major biochemical reactions and transport processes in lung mitochondria. A general framework was developed to model those biochemical reactions and transport processes. Intrinsic model parameters such as binding constants were estimated using previously published isolated enzymes and transporters kinetic data. Extrinsic model parameters such as maximal reaction and transport velocities were estimated by fitting the integrated bioenergetics model to published and new tricarboxylic acid cycle and respirometry data measured in isolated rat lung mitochondria. The integrated model was then validated by assessing its ability to predict experimental data not used for the estimation of the extrinsic model parameters. For example, the model was able to predict reasonably well the substrate and temperature dependency of mitochondrial oxygen consumption, kinetics of NADH redox status, and the kinetics of mitochondrial accumulation of the cationic dye rhodamine 123, driven by mitochondrial membrane potential, under different respiratory states. The latter required the coupling of the integrated bioenergetics model to a pharmacokinetic model for the mitochondrial uptake of rhodamine 123 from buffer. The integrated bioenergetics model provides a mechanistic and quantitative framework for 1) integrating experimental data from isolated lung mitochondria under diverse experimental conditions, and 2) assessing the impact of a change in one or more mitochondrial processes on overall lung mitochondrial bioenergetics. In addition, the model provides important insights into the bioenergetics and respiration of lung mitochondria and how they differ from those of mitochondria from other organs. To the best of our knowledge, this model is the first for the bioenergetics of isolated lung mitochondria.