粒体自噬
品脱1
变位酶
线粒体
帕金
生物
斑马鱼
细胞生物学
粒线体疾病
氧化应激
甲基丙二酸尿症
癌症研究
遗传学
疾病
帕金森病
线粒体DNA
医学
内分泌学
基因
内科学
维生素B12
甲基丙二酸
自噬
细胞凋亡
作者
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 Díaz,Carlos T. Moraes,Diego di Bernardo,Matthias R. Baumgartner,Olivier Devuyst
标识
DOI:10.1038/s41467-020-14729-8
摘要
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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