ZFIN ID: ZDB-PUB-200225-3
Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency
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.
Date: 2020
Source: Nature communications   11: 970 (Journal)
Registered Authors: Devuyst, Oliver, Luciani, Alessandro
Keywords: none
MeSH Terms:
  • 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
PubMed: 32080200 Full text @ Nat. Commun.
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.