Reference - Detail
|Author||Luciani A, Schumann A, Berquez M, Chen Z, Nieri D, Failli M, Debaix H, Festa BP, Tokonami N, Raimondi A, Cremonesi A, Carrella D, Forny P, Kölker S, Diomedi Camassei F, Diaz F, Moraes CT, Di Bernardo D, Baumgartner MR, Devuyst O.|
|Title||Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency.|
Deregulation of mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders. Methylmalonic acidemia (MMA) is one of the most common inherited metabolic disorders, due to deficiency of the mitochondrial methylmalonyl-coenzyme A mutase (MMUT). How MMUT deficiency triggers cell damage remains unknown, preventing the development of disease-modifying therapies. Here we combine genetic and pharmacological approaches to demonstrate that MMUT deficiency induces metabolic and mitochondrial alterations that are exacerbated by anomalies in PINK1/Parkin-mediated mitophagy, causing the accumulation of dysfunctional mitochondria that trigger epithelial stress and ultimately cell damage. Using drug-disease network perturbation modelling, we predict targetable pathways, whose modulation repairs mitochondrial dysfunctions in patient-derived cells and alleviate phenotype changes in mmut-deficient zebrafish. These results suggest a link between primary MMUT deficiency, diseased mitochondria, mitophagy dysfunction and epithelial stress, and provide potential therapeutic perspectives for MMA.
|MeSH||Alkyl and Aryl Transferases / deficiency Alkyl and Aryl Transferases / genetics Amino Acid Metabolism, Inborn Errors / genetics Amino Acid Metabolism, Inborn Errors / metabolism* Amino Acid Metabolism, Inborn Errors / pathology* Animals Disease Models, Animal Epithelial Cells / metabolism Epithelial Cells / pathology Female Gene Knockout Techniques Humans Male Membrane Proteins / deficiency Membrane Proteins / genetics Metabolism, Inborn Errors / genetics Metabolism, Inborn Errors / metabolism* Metabolism, Inborn Errors / pathology* Methylmalonyl-CoA Mutase / deficiency* Methylmalonyl-CoA Mutase / genetics Methylmalonyl-CoA Mutase / metabolism Mice Mice, Knockout Mitochondrial Diseases / genetics Mitochondrial Diseases / metabolism* Mitochondrial Diseases / pathology* Mitophagy / genetics Mitophagy / physiology* Protein Kinases / genetics Protein Kinases / metabolism Stress, Physiological Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism Zebrafish|