Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

PURPOSE: To understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease. METHODS: We identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons. RESULTS: The patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid, and quinolinic acid, which was confirmed in the patient's urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis. CONCLUSION: Mitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy-like disease

Model

Metabolic model in SBML forma

Model

Metabolic model in SBML forma

Source code from Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism

Matlab script to generate the metabolic prediction

Supplementary material from "Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism"

Metabolism is the only biological system that can be fully modelled at genome scale. As a result, metabolic models have been increasingly used to study the molecular mechanisms of various diseases. Hypoxia, a low-oxygen tension, is a well-known characteristic of many cancer cells. Pyruvate dehydrogenase controls the flux of metabolites between glycolysis and the tricarboxylic acid cycle and is a key enzyme in metabolic reprogramming in cancer metabolism. Here, we develop and manually curate a constraint-based metabolic model to investigate the mechanism of pyruvate dehydrogenase under hypoxia. Our results characterize the activity of pyruvate dehydrogenase and its decline during hypoxia. This results in lactate accumulation, consistent with recent hypoxia studies and a well-known feature in cancer metabolism. We apply machine-learning techniques on the flux datasets to identify reactions that drive variations. We also identify distinct features on the structure of the variable and individual components. Our results provide a framework for future studies by integrating multi-omics data to predict condition-specific metabolic phenotypes under hypoxia

Model

Metabolic model in SBML forma

Source code from Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism

Matlab script to generate the metabolic prediction

Flux distribution results from Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism

Excel file containing reactions (using KEGG identifiers) in the model and flux values from various conditions

Flux distribution results from Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism

Excel file containing reactions (using KEGG identifiers) in the model and flux values from various conditions