SWATH-MS reveals tissue-specific proteomic changes in a Leigh syndrome mouse model

Mutations in the Ndufs4 gene encoding the accessory subunit of complex I (CI) of the mitochondrial oxidative phosphorylation (OXPHOS) system, are the most common causes of Leigh Syndrome (LS). LS is a severe infantile neurodegenerative disorder characterised by various clinical phenotypes ranging from ataxia, cardiomyopathy, swallowing difficulties, visual problems, psychomotor regression to fatal respiratory failure. The mechanistic processes contributing to the onset and progression of these clinical manifestations remain poorly understood. This study investigates tissue-specific proteomic changes in a mouse model of LS using quantitative proteomics as a hypothesis-generating technique. Six distinct tissues, namely three brain regions (brainstem, cerebellum, olfactory bulb), heart, kidney, and liver, were collected from the LS mouse model (Ndufs4 KO mice) and compared to wild type (WT) controls using SWATH-MS analysis as a data acquisition method. Functional enrichment analysis revealed distinct tissue-specific cellular responses which include a shift toward amino acid metabolism in the heart, increased mitochondrial translation in the kidney, and alterations in phase II detoxification pathways in the liver. Our results unravel candidate mechanisms for tissue-specific vulnerability and highlight the regulation of PTEN gene transcription as potential driver of neurodegeneration. These findings provide data-driven hypotheses for tissue-specific vulnerability in LS, highlighting potential mechanisms and therapeutic targets. This study established a foundation for future hypothesis-driven research into the tissue-specific pathophysiology of mitochondrial disease.