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

Alessandro Luciani (), Anke Schumann, Marine Berquez, Zhiyong Chen, Daniela Nieri, Mario Failli, Huguette Debaix, Beatrice Paola Festa, Natsuko Tokonami, Andrea Raimondi, Alessio Cremonesi, Diego Carrella, Patrick Forny, Stefan Kölker, Francesca Diomedi Camassei, Francisca Diaz, Carlos T. Moraes, Diego Di Bernardo, Matthias R. Baumgartner and Olivier Devuyst ()
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Alessandro Luciani: University of Zurich
Anke Schumann: University of Zurich
Marine Berquez: University of Zurich
Zhiyong Chen: University of Zurich
Daniela Nieri: University of Zurich
Mario Failli: University of Eastern Finland
Huguette Debaix: University of Zurich
Beatrice Paola Festa: University of Zurich
Natsuko Tokonami: University of Zurich
Andrea Raimondi: Experimental Imaging Center
Alessio Cremonesi: University Children’s Hospital Zurich
Diego Carrella: Telethon Institute of Genetics and Medicine
Patrick Forny: University Children’s Hospital
Stefan Kölker: University Children’s Hospital Heidelberg
Francesca Diomedi Camassei: Bambino Gesù Children’s Hospital
Francisca Diaz: University of Miami Miller School of Medicine
Carlos T. Moraes: University of Miami Miller School of Medicine
Diego Di Bernardo: Telethon Institute of Genetics and Medicine
Matthias R. Baumgartner: University Children’s Hospital
Olivier Devuyst: University of Zurich

Nature Communications, 2020, vol. 11, issue 1, 1-21

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14729-8

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