Data-Independent Acquisition-Based Quantitative Proteomic Analysis of m.3243A>G MELAS Reveals Novel Potential Pathogenesis and Therapeutic Targets

Abstract Background The pathogenesis of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS) syndrome is not completely understood. The m.3243A > G mutation responsible for 80% MELAS patients affects proteins with undetermined functions. Therefore, we performed quantitative proteomic analysis on skeletal muscle specimens from MELAS patients. Methods We recruited 10 patients with definitive MELAS and 10 controls matched by age and gender of MELAS patients for comparison. We performed nanospray liquid chromatography-mass spectrometry (LC-MS) based proteomic analysis in the data-independent acquisition (DIA) modes, followed by the statistical analysis to reveal the differentially expressed proteins. Results We identified 128 differential proteins between MELAS and controls, including 68 for down-regulation and 60 for up-regulation. We studied the differential proteins involved in oxidative stress and indicated a highly significant up-regulation of heat shock protein beta-1 (HSPB1), alpha-crystallin B chain (CRYAB) and heme oxygenase 1 (HMOX1) but a decrease of glucose-6-phosphate dehydrogenase (G6PD) and selenoprotein P (SEPP1). KEGG pathway analysis and gene ontology (GO) evaluation revealed that the phagosome, proliferator-activated receptors (PPAR) signaling pathway and ribosome showed significant enrichment. Conclusions The results revealed that the imbalance between oxidative stress and antioxidant defense, activation of autophagosomes and abnormal metabolism of mitochondrial ribosome proteins played an important role in m.3243A > G MELAS. The combination of proteomic profiling and bioinformatics analysis could contribute novel molecular networks to the pathogenesis of MELAS in a comprehensive manner.