Metabolic flexibility of mitochondrial respiratory chain disorders predicted by computer modelling.

TitleMetabolic flexibility of mitochondrial respiratory chain disorders predicted by computer modelling.
Publication TypeJournal Article
Year of Publication2016
AuthorsZieliński, ŁP, Smith, AC, Smith, AG, Robinson, AJ
JournalMitochondrion
Volume31
Pagination45-55
Date Published2016 Nov
ISSN1872-8278
KeywordsAdenosine Triphosphate, Computer Simulation, Cytochrome-c Oxidase Deficiency, Electron Transport Complex I, Electron Transport Complex II, Electron Transport Complex III, Humans, Mitochondria, Myocytes, Cardiac
Abstract

Mitochondrial respiratory chain dysfunction causes a variety of life-threatening diseases affecting about 1 in 4300 adults. These diseases are genetically heterogeneous, but have the same outcome; reduced activity of mitochondrial respiratory chain complexes causing decreased ATP production and potentially toxic accumulation of metabolites. Severity and tissue specificity of these effects varies between patients by unknown mechanisms and treatment options are limited. So far most research has focused on the complexes themselves, and the impact on overall cellular metabolism is largely unclear. To illustrate how computer modelling can be used to better understand the potential impact of these disorders and inspire new research directions and treatments, we simulated them using a computer model of human cardiomyocyte mitochondrial metabolism containing over 300 characterised reactions and transport steps with experimental parameters taken from the literature. Overall, simulations were consistent with patient symptoms, supporting their biological and medical significance. These simulations predicted: complex I deficiencies could be compensated using multiple pathways; complex II deficiencies had less metabolic flexibility due to impacting both the TCA cycle and the respiratory chain; and complex III and IV deficiencies caused greatest decreases in ATP production with metabolic consequences that parallel hypoxia. Our study demonstrates how results from computer models can be compared to a clinical phenotype and used as a tool for hypothesis generation for subsequent experimental testing. These simulations can enhance understanding of dysfunctional mitochondrial metabolism and suggest new avenues for research into treatment of mitochondrial disease and other areas of mitochondrial dysfunction.

DOI10.1016/j.mito.2016.09.003
Alternate JournalMitochondrion
Citation Key10.1016/j.mito.2016.09.003
PubMed ID27697518
PubMed Central IDPMC5115619
Grant ListMC_U105674181 / / Medical Research Council / United Kingdom