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.

Dysregulation of metabolic‐associated pathways in muscle of breast cancer patients: preclinical evaluation of interleukin‐15 targeting fatigue

“…Multiple genes within the mitochondrial ETC, specifically within complexes I, IV and V, were down‐regulated, which would potentially contribute to mitochondrial dysfunction and reduced ATP available to fuel muscle contraction . Additionally, alterations in energy metabolism through the down‐regulation of PPAR‐related signalling would also contribute to altered mitochondrial function .…”

“…Multiple genes within the mitochondrial ETC, specifically within complexes I, IV and V, were down-regulated, which would potentially contribute to mitochondrial dysfunction and reduced ATP available to fuel muscle contraction. 43,44 Additionally, alterations in energy metabolism through the down-regulation of PPAR-related signalling would also contribute to altered mitochondrial function. 24,45,46 Collectively, the down-regulation of mitochondrial genes as well as the predicted down-regulation of β-oxidation through alterations of a gene network including PPARα, PPARγ, and PGC-1α provides a biochemical mechanism for the reported greater fatigue experienced in breast cancer patients.…”

BRAWNIN: A sORF-encoded Peptide Essential for Vertebrate Mitochondrial Complex III Assembly

“…Lactate accumulation is caused by decreased pyruvate oxidation secondary to mitochondrial deficiency and is frequently used as a diagnostic symptom for patients with mitochondrial diseases 26 . To understand how these perturbations could be related to CIII deficiency, we turned to MitoCore, a metabolic flux model that simulates over 300 mitochondrial reactions in a human cardiomyocyte using flux balance analysis 27 . By blocking each reaction in turn, and simulating 5000 feasible flux states for each possible blockage, we found that inhibiting CIII and CIV (but not CII) flux caused the largest, most biologically plausible increase in succinate and lactate (as inferred from the export rate of the two metabolites) ( Fig.…”

“…The Mitocore model was downloaded in SBML format from 27 . Each of the 485 reactions in the model was blocked (setting upper and lower bounds of permissible flux to zero), one reaction at a time, and the ATP production (Reaction ID: "OF_ATP_MitoCore") was constrained to have a flux > 90% of the theoretical capacity of the blocked model.…”

MitoCore: A curated constraint-based model for simulating human central metabolism

“…We previously applied this approach for our iAS253 model of the mitochondrion, which we used to simulate metabolic diseases of the tricarboxylic acid cycle [16]. This model was then used as a basis to simulate other disorders including hypoxia during cardiac ischemia [17], fumarate hydratase deficiency [18] and common diseases of the mitochondrial electron transport chain [19]. These simulation results were used to generate detailed mechanistic hypotheses for data interpretation and to design further experiments.…”