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

Alessandro Luciani,Stefan Kölker,Francesca Diomedi Camassei,Marine Berquez,Daniela Nieri,Natsuko Tokonami,Anke Schumann,Andrea Raimondi,Diego Di Bernardo,Mario Failli,Alessio Cremonesi,Matthias R Baumgartner,Carlos T Moraes,Francisca Díaz ,Diego Carrella,Huguette Debaix,Zhiyong Chen,Beatrice Paola Festa,Patrick Forny,Olivier Devuyst

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.

Highlights

Deregulation of mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders
As methylmalonyl-coenzyme A mutase (MMUT) is robustly expressed within the mitochondria of kidney tubular cells (Supplementary Fig. 1a‒e), we first investigated the consequences of MMUT deficiency on mitochondrial function and homeostasis in these cells
Transmission electron microscopy (TEM) analyses revealed that mitochondria, which appear as an interconnected meshwork of elongated or curvilinear organelles in control cells, were fragmented or characterized by a prominent rod-like shape with perturbed cristae organization in Methylmalonic acidemia (MMA) cells (Fig. 1e) and in the kidneys of a patient with MMA (Fig. 1f), in line with recent studies showing an abnormal mitochondrial ultrastructure in both kidney and explanted livers of patients with MMA26

Summary

Introduction

Deregulation of mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders. 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 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. Cells possess quality control systems to maintain a requisite number of functional mitochondria to meet the energy demands[20] These pathways concur to eliminate damaged mitochondrial proteins or dysfunctional parts of mitochondrial network by autophagy Abnormal mitochondria with disorganized cristae have been described in kidney cells[25] and biopsies from MMA patients[10,26], suggesting an involvement of mitochondrial quality control mechanisms in the disease

Methods

Results

Conclusion