NEW PUBLICATION - Cellular and computational models reveal environmental and metabolic interactions in MMUT-type methylmalonic aciduria
Methylmalonyl-coenzyme A (CoA) mutase (MMUT)-type methylmalonic aciduria is a rare inherited metabolic disease caused by the loss of function of the MMUT enzyme. Patients develop symptoms resembling those of primary mitochondrial disorders, but the underlying causes of mitochondrial dysfunction remain unclear. Here, we examined environmental and genetic interactions in MMUT deficiency using a combination of computational modeling and cellular models to decipher pathways interacting with MMUT. Immortalized fibroblast (hTERT BJ5ta) MMUT-KO (MUTKO) clones displayed a mild mitochondrial impairment in standard glucose-based medium, but they did not to show increased reliance on respiratory metabolism nor reduced growth or viability. Consistently, our modeling predicted MUTKO specific growth phenotypes only for lower extracellular glutamine concentrations. Indeed, two of three MMUT-deficient BJ5ta cell lines showed a reduced viability in glutamine-free medium. Further, growth on 183 different carbon and nitrogen substrates identified increased NADH (nicotinamide adenine dinucleotide) metabolism of BJ5ta and HEK293 MUTKO cells compared with controls on purine- and glutamine-based substrates. With this knowledge, our modeling predicted 13 reactions interacting with MMUT that potentiate an effect on growth, primarily those of secondary oxidation of propionyl-CoA, oxidative phosphorylation and oxygen diffusion. Of these, we validated 3-hydroxyisobutytyl-CoA hydrolase (HIBCH) in the secondary propionyl-CoA oxidation pathway. Altogether, these results suggest compensation for the loss of MMUT function by increasing anaplerosis through glutamine or by diverting flux away from MMUT through the secondary propionyl-CoA oxidation pathway, which may have therapeutic relevance.
- NEW PUBLICATION - Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency
- NEW PUBLICATION - Caregiver burden, and parents' perception of disease severity determine health-related quality of life in paediatric patients with intoxication-type inborn errors of metabolism
- NEW PUBLICATION - Tubular cell plasticity—new hope for autosomal dominant polycystic kidney disease?
- Prof. Nikola Biller-Andorno became a member of the EU ethics group!
- NEW PUBLICATION - Defective Cystinosin, Aberrant Autophagy−Endolysosome Pathways, and Storage Disease: Towards Assembling the Puzzle
- Congratulations to the ITINERARE Grants winners!
- NEW PUBLICATION - AQP1 Promoter Variant, Water Transport and Outcome in Peritoneal Dialysis
- NEW PUBLICATION - Spectrum and characterization of bi-allelic variants in MMAB causing cblB-type methylmalonic aciduria
- NEW PUBLICATION - Mendelian randomization to assess causality between uromodulin, blood pressure and chronic kidney disease
- Registration to the ITINERARE Symposium 2021 is open!
- NEW PUBLICATION - Mitochondrial disease, mitophagy, and cellular distress in methylmalonic acidemia
- ITINERARE@Scientifica 2021
- NEW PUBLICATION - An international cohort study spanning five decades assessed outcomes of nephropathic cystinosis
- NEW PUBLICATION - Absence of MMACHC in peripheral retinal cells does not lead to an ocular phenotype in mice
- NEW PUBLICATION - A systematic review of moral reasons on orphan drug reimbursement
- NEW PUBLICATION - Assessing transport across the peritoneal membrane: Precision medicine in dialysis
- NEW PUBLICATION - Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness
- NEW PUBLICATION - Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision
- NEW PUBLICATION - Receptor-Mediated Endocytosis and Differentiation in Proximal Tubule Cell Systems
- NEW PUBLICATION - PIEZO2, a mechanosensor in the urinary bladder
- ITINERARE kick-off meeting May 18th (closed event)
- URPP kick-off event March 23rd