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

Nat Commun. 2020 Feb 20;11(1):970. doi: 10.1038/s41467-020-14729-8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

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

Substances

  • Membrane Proteins
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Alkyl and Aryl Transferases
  • COX10 protein, mouse
  • Protein Kinases
  • PTEN-induced putative kinase
  • Methylmalonyl-CoA Mutase

Supplementary concepts

  • Methylmalonic acidemia
  • Methylmalonyl-Coenzyme A mutase deficiency