title: Metabolic flexibility of mitochondrial respiratory chain disorders predicted by computer modelling.
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.
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK; University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0SP, UK.
authors.forename: Łukasz P
authors.initials: ŁP
authors.lastname: Zieliński
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Smith
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Smith
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK. Electronic address: alan.robinson@mrc-mbu.cam.ac.uk.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Robinson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D003198:Computer Simulation; D030401:Cytochrome-c Oxidase Deficiency; D042967:Electron Transport Complex I / Q000172:deficiency*; D042963:Electron Transport Complex II / Q000172:deficiency*; D014450:Electron Transport Complex III / Q000172:deficiency*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*
chemical_list: D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III
keywords: Electron transport chain; Flux balance analysis; Metabolism; Mitochondrial disease