Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency.
- Luciani A Institute of Physiology and NCCR Kidney.CH, University of Zurich, 8057, Zurich, Switzerland. alessandro.luciani@uzh.ch.
- Schumann A Institute of Physiology and NCCR Kidney.CH, University of Zurich, 8057, Zurich, Switzerland.
- Berquez M Institute of Physiology and NCCR Kidney.CH, University of Zurich, 8057, Zurich, Switzerland.
- Chen Z Institute of Physiology and NCCR Kidney.CH, University of Zurich, 8057, Zurich, Switzerland.
- Nieri D Institute of Physiology and NCCR Kidney.CH, University of Zurich, 8057, Zurich, Switzerland.
- Failli M Department of Biomedicine, University of Eastern Finland, 70211, Kuopio, Finland.
- Debaix H Institute of Physiology and NCCR Kidney.CH, University of Zurich, 8057, Zurich, Switzerland.
- Festa BP Institute of Physiology and NCCR Kidney.CH, University of Zurich, 8057, Zurich, Switzerland.
- Tokonami N Institute of Physiology and NCCR Kidney.CH, University of Zurich, 8057, Zurich, Switzerland.
- Raimondi A San Raffaele Scientific Institute, Experimental Imaging Center, 20132, Milan, Italy.
- Cremonesi A Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, 8032, Zurich, Switzerland.
- Carrella D Telethon Institute of Genetics and Medicine, Pozzuoli, 80078, Naples, Italy.
- Forny P Division of Metabolism and Children's Research Center, University Children's Hospital, 8032, Zurich, Switzerland.
- Kölker S Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, 69120, Heidelberg, Germany.
- Diomedi Camassei F Department of Laboratories-Pathology Unit, Bambino Gesù Children's Hospital, 00165, Rome, Italy.
- Diaz F Department of Neurology, University of Miami Miller School of Medicine, 33136, Miami, FL, USA.
- Moraes CT Department of Neurology, University of Miami Miller School of Medicine, 33136, Miami, FL, USA.
- Di Bernardo D Telethon Institute of Genetics and Medicine, Pozzuoli, 80078, Naples, Italy.
- Baumgartner MR Division of Metabolism and Children's Research Center, University Children's Hospital, 8032, Zurich, Switzerland.
- Devuyst O Institute of Physiology and NCCR Kidney.CH, University of Zurich, 8057, Zurich, Switzerland. olivier.devuyst@uzh.ch.
- 2020-02-22
Published in:
- Nature communications. - 2020
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
English
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1038/s41467-020-14729-8
- PMID 32080200
- Persistent URL
- https://folia.unifr.ch/global/documents/297323
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