PUBLICATION
Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency
- Authors
- Luciani, A., Schumann, A., Berquez, M., Chen, Z., Nieri, D., Failli, M., Debaix, H., Festa, B.P., Tokonami, N., Raimondi, A., Cremonesi, A., Carrella, D., Forny, P., Kölker, S., Diomedi Camassei, F., Diaz, F., Moraes, C.T., Di Bernardo, D., Baumgartner, M.R., Devuyst, O.
- ID
- ZDB-PUB-200225-3
- Date
- 2020
- Source
- Nature communications 11: 970 (Journal)
- Registered Authors
- Devuyst, Oliver, Luciani, Alessandro
- Keywords
- none
- MeSH Terms
-
- Stress, Physiological
- Zebrafish
- Disease Models, Animal
- Metabolism, Inborn Errors/genetics
- Metabolism, Inborn Errors/metabolism*
- Metabolism, Inborn Errors/pathology*
- Mice
- Male
- Protein Kinases/genetics
- Protein Kinases/metabolism
- Gene Knockout Techniques
- Female
- Mice, Knockout
- Ubiquitin-Protein Ligases/genetics
- Ubiquitin-Protein Ligases/metabolism
- Animals
- Alkyl and Aryl Transferases/deficiency
- Alkyl and Aryl Transferases/genetics
- Mitochondrial Diseases/genetics
- Mitochondrial Diseases/metabolism*
- Mitochondrial Diseases/pathology*
- Mitophagy/genetics
- Mitophagy/physiology*
- Amino Acid Metabolism, Inborn Errors/genetics
- Amino Acid Metabolism, Inborn Errors/metabolism*
- Amino Acid Metabolism, Inborn Errors/pathology*
- Membrane Proteins/deficiency
- Membrane Proteins/genetics
- Methylmalonyl-CoA Mutase/deficiency*
- Methylmalonyl-CoA Mutase/genetics
- Methylmalonyl-CoA Mutase/metabolism
- Epithelial Cells/metabolism
- Epithelial Cells/pathology
- Humans
- PubMed
- 32080200 Full text @ Nat. Commun.
Citation
Luciani, A., Schumann, A., Berquez, M., Chen, Z., Nieri, D., Failli, M., Debaix, H., Festa, B.P., Tokonami, N., Raimondi, A., Cremonesi, A., Carrella, D., Forny, P., Kölker, S., Diomedi Camassei, F., Diaz, F., Moraes, C.T., Di Bernardo, D., Baumgartner, M.R., Devuyst, O. (2020) Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency. Nature communications. 11:970.
Abstract
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.
Errata / Notes
This article is corrected by ZDB-PUB-220906-199 .
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping