Data-independent acquisition-based quantitative proteomic analysis of m.3243A>G MELAS reveals novel potential pathogenesis and therapeutic targets

The pathogenesis of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS) syndrome has not been fully elucidated. The m.3243A > G mutation which is responsible for 80% MELAS patients affects proteins with undetermined functions. Therefore, we performed quantitative proteomic analysis on skeletal muscle specimens from MELAS patients. We recruited 10 patients with definitive MELAS and 10 age- and gender- matched controls. Proteomic analysis based on nanospray liquid chromatography-mass spectrometry (LC-MS) was performed using data-independent acquisition (DIA) method and differentially expressed proteins were revealed by bioinformatics analysis. We identified 128 differential proteins between MELAS and controls, including 68 down-regulated proteins and 60 up-regulated proteins. The differential proteins involved in oxidative stress were identified, including heat shock protein beta-1 (HSPB1), alpha-crystallin B chain (CRYAB), heme oxygenase 1 (HMOX1), glucose-6-phosphate dehydrogenase (G6PD) and selenoprotein P. Gene ontology and kyoto encyclopedia of genes and genomes pathway analysis showed significant enrichment in phagosome, ribosome and peroxisome proliferator-activated receptors (PPAR) signaling pathway. The imbalance between oxidative stress and antioxidant defense, the activation of autophagosomes, and the abnormal metabolism of mitochondrial ribosome proteins (MRPs) might play an important role in m.3243A > G MELAS. The combination of proteomic and bioinformatics analysis could contribute potential molecular networks to the pathogenesis of MELAS in a comprehensive manner.

Automated summary

The pathogenesis of MELAS syndrome, which involves mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, remains unclear. This study performed proteomic analysis on skeletal muscle specimens from MELAS patients and identified differential proteins related to oxidative stress, as well as pathways involving phagosome, ribosome, and peroxisome proliferator-activated receptors (PPAR). These findings suggest that the imbalance between oxidative stress and antioxidant defense, as well as abnormal metabolism of mitochondrial ribosome proteins, may play important roles in the development of MELAS syndrome.