Small molecule oxybutynin rescues proliferative capacity of complex III-defective MPCs
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE282462 | GEO | 2024/11/25
REPOSITORIES: GEO
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efforts in recent decades have established the core protein componentry of these organelles
and have linked their dysfunction to over 150 distinct disorders. However, hundreds of
mitochondrial proteins still lack clear functions, and ~40% of mitochondrial disorders
remain unresolved. To establish a more complete functional compendium of human
mitochondrial proteins, we profiled 203 CRISPR-mediated HAP1 cell knockout lines
using mass spectrometry-based multi-omics analyses. This effort generated ~8.2 million
distinct biomolecule measurements, providing a deep survey of the cellular responses to
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protein function. Guided by these data, we discovered that PYURF is a SAM-dependent
methyltransferase chaperone that supports both complex I assembly and coenzyme Q
biosynthesis, and that is disrupted in a previously unresolved multisystemic mitochondrial
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OxPhos integrity and established RAB5IF as the second gene harboring pathogenic
variants causing cerebrofaciothoracic dysplasia. Our data - which can be explored through
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Project description:This model is from the article:
A metabolic model of the mitochondrion and its use in modelling diseases of the tricarboxylic acid cycle.
Smith AC, Robinson AJ. BMC Syst Biol.
2011 Jun 29;5(1):102. 21714867
,
Abstract:
BACKGROUND:Mitochondria are a vital component of eukaryotic cells and their dysfunction is implicated in a large number of metabolic, degenerative and age-related human diseases. The mechanism or these disorders can be difficult to elucidate due to the inherent complexity of mitochondrial metabolism. To understand how mitochondrial metabolic dysfunction contributes to these diseases, a metabolic model of a human heart mitochondrion was created.
RESULTS:
A new model of mitochondrial metabolism was built on the principle of metabolite availability using MitoMiner, a mitochondrial proteomics database, to evaluate the subcellular localisation of reactions that have evidence for mitochondrial localisation. Extensive curation and manual refinement was used to create a model called iAS253, containing 253 reactions, 245 metabolites and 89 transport steps across the inner mitochondrial membrane. To demonstrate the predictive abilities of the model, flux balance analysis was used to calculate metabolite fluxes under normal conditions and to simulate three metabolic disorders that affect the TCA cycle: fumarase deficiency, succinate dehydrogenase deficiency and alpha-ketoglutarate dehydrogenase deficiency.
CONCLUSION:
The results of simulations using the new model corresponded closely with phenotypic data under normal conditions and provided insight into the complicated and unintuitive phenotypes of the three disorders, including the effect of interventions that may be of therapeutic benefit, such as low glucose diets or amino acid supplements. The model offers the ability to investigate other mitochondrial disorders and can provide the framework for the integration of experimental data in future studies.
Created by Anthony C. Smith (Mon Mar 14 11:03:11 2011) MRC - Mitochondrial Biology Unit, Cambridge, UK. acs@mrc-mbu.cam.ac.uk
This metabolic network is a stocihiometric model of a human heart mitochondrion. Identifiers are KEGG Ids.
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
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To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1106160000 | BioModels