TY - JOUR
T1 - Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency
AU - Luciani, Alessandro
AU - Schumann, Anke
AU - Berquez, Marine
AU - Chen, Zhiyong
AU - Nieri, Daniela
AU - Failli, Mario
AU - Debaix, Huguette
AU - Festa, Beatrice Paola
AU - Tokonami, Natsuko
AU - Raimondi, Andrea
AU - Cremonesi, Alessio
AU - Carrella, Diego
AU - Forny, Patrick
AU - Kölker, Stefan
AU - Diomedi Camassei, Francesca
AU - Diaz, Francisca
AU - Moraes, Carlos T.
AU - Di Bernardo, Diego
AU - Baumgartner, Matthias R.
AU - Devuyst, Olivier
N1 - Funding Information:
We thank Gery Barmettler, Nadine Naegele and Benjamin Klormann for technical assistance, and the Center for Microscopy and Image Analysis at the University of Zurich for providing equipment and confocal and electron microscopy assistance as well as the Bioinformatics core Facility of the Telethon Institute of Genetics and Medicine for help with bioinformatics analysis. We also thank Claire Boulange, Manuja Kaluarachchi, Elisabetta Biglieri and Lubor Borsig, Luca Scorrano, Elena Ziviani, Leonardo Salviati and Francesco Emma for their advice and fruitful discussions. We acknowledge Euro-BioImaging (www.eurobioimaging.eu) for providing access to imaging technologies and services via the Italian Node (ALEMBIC, Milan, Italy). We are grateful to Fonds National de la Recherche Scientifique and the Fonds de la Recherche Scientifique Médicale (Brussels, Belgium), the European Community’s Seventh Framework Programme (FP7/ 2007–2013) under grant agreement number 305608 (EURenOmics) and under the grant agreement number 608847 (IKPP2), the Cystinosis Research Foundation (Irvine, CA, USA), the Swiss National Science Foundation (project grant 31003A-169850), the clinical research priority programs (KFSP) radiz (Rare Disease Initiative Zurich) and Molecular Imaging Network Zurich (MINZ) at the University of Zurich, the Swiss National Centre of Competence in Research (NCCR) Kidney Control of Homeostasis (Kidney.CH) for support and Junior Grant (to A.L.). A.S. was supported by grants from Swiss National Science Foundation (project grants, 310030_146490 and 310030_189044, respectively) and the Wolfermann-Nägeli Shiftung.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-14729-8
DO - 10.1038/s41467-020-14729-8
M3 - Article
C2 - 32080200
AN - SCOPUS:85079768219
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 970
ER -