Fig. 10

In wild-type kidney cells (left), mitochondrial stress (e.g. treatment with Rotenone) stimulates PINK1-induced translocation of Parkin to damaged mitochondria. This triggers mitophagy and the subsequent disposal of dysfunctional mitochondria through autophagy–lysosome degradation systems, thereby safeguarding the homeostasis and function of the mitochondrial network. By contrast, in MMA-affected kidney cells (right), the impaired PINK/Parkin-mediated mitophagy impedes the delivery of damaged mitochondria and their degradation by autophagy‒lysosome pathways. This leads to accumulation of MMA-diseased mitochondria and exacerbates the mitochondrial alterations induced by MMUT deficiency, including accumulation of toxic metabolites, collapsed mitochondrial membrane potential (Δψ_m), and abnormal energetic profiling and increased mitochondrial ROS. These mitochondrial alterations generate epithelial stress, causing ultimately cell damage (e.g. LCN2 overproduction). Drug–disease network perturbation modelling, based on transcriptome-wide profiles from MMA patient-derived kidney cells against a large compendium of gene signatures derived from 1309 small bioactive drug compounds, identifies targetable disease-relevant cell biological pathways. The modulation of the identified targets (e.g. treatment with mitochondria-targeted ROS scavengers MT or MitoQ) repairs mitochondrial dysfunctions, neutralizes epithelial stress and cell damage in MMA cells, and improves disease-relevant phenotypes in mmut–deficient zebrafish.