Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency: Nature Communications

A. Luciani, A. Schumann, M. Berquez, Z. Chen, D. Nieri, M. Failli, H. Debaix, B.P. Festa, N. Tokonami, A. Raimondi, A. Cremonesi, D. Carrella, P. Forny, S. Kölker, F. Diomedi Camassei, F. Diaz, C.T. Moraes, D. Di Bernardo, M.R. Baumgartner, O. Devuyst

Research output: Contribution to journalArticlepeer-review


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. © 2020, The Author(s).
Original languageEnglish
JournalNat. Commun.
Issue number1
Publication statusPublished - 2020


  • methylmalonic acid
  • methylmalonyl coenzyme A mutase
  • COX10 protein, mouse
  • membrane protein
  • parkin
  • protein kinase
  • PTEN-induced putative kinase
  • transferase
  • ubiquitin protein ligase
  • cell
  • cyprinid
  • disease
  • drug
  • enzyme
  • enzyme activity
  • metabolism
  • mitochondrion
  • phenotype
  • animal cell
  • animal experiment
  • animal model
  • apoptosis
  • Article
  • autophagosome
  • biogenesis
  • cell metabolism
  • cell viability
  • confocal laser scanning microscopy
  • confocal microscopy
  • controlled study
  • disorders of mitochondrial functions
  • DNA damage
  • drug induced disease
  • electron microscopy
  • electron transport
  • enzyme deficiency
  • fluorescence microscopy
  • gene expression
  • image analysis
  • immunoblotting
  • immunofluorescence
  • immunohistochemistry
  • kidney tubule cell
  • metabolic disorder
  • methylmalonic acidemia
  • microarray analysis
  • mitochondrial dynamics
  • mitochondrial membrane
  • mitochondrial respiration
  • mitophagy
  • mouse
  • nonhuman
  • oxidative stress
  • oxygen consumption
  • stress
  • transmission electron microscopy
  • zebra fish
  • animal
  • disease model
  • disorders of amino acid and protein metabolism
  • epithelium cell
  • female
  • gene knockout
  • genetics
  • human
  • inborn error of metabolism
  • knockout mouse
  • male
  • pathology
  • physiological stress
  • physiology
  • Danio rerio
  • Alkyl and Aryl Transferases
  • Amino Acid Metabolism, Inborn Errors
  • Animals
  • Disease Models, Animal
  • Epithelial Cells
  • Female
  • Gene Knockout Techniques
  • Humans
  • Male
  • Membrane Proteins
  • Metabolism, Inborn Errors
  • Methylmalonyl-CoA Mutase
  • Mice
  • Mice, Knockout
  • Mitochondrial Diseases
  • Mitophagy
  • Protein Kinases
  • Stress, Physiological
  • Ubiquitin-Protein Ligases
  • Zebrafish


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