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Data-Independent Acquisition-Based Quantitative Proteomic Analysis of M.3243A>G MELAS Reveals Novel Potential Pathogenesis An

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Data-Independent Acquisition-Based Quantitative Proteomic Analysis of M.3243A>G MELAS Reveals Novel Potential Pathogenesis An Data-Independent Acquisition-Based Quantitative Proteomic Analysis of m.3243A>G MELAS Reveals Novel Potential Pathogenesis and Therapeutic Targets Xueli Chang First Hospital of Shanxi Medical University Wei Zhang First Hospital of Shanxi Medical University Chuanqiang Pu Chinese PLA General Hospital Qiang Shi Chinese PLA General Hospital Juan Wang First Hospital of Shanxi Medical University Jing Zhang First Hospital of Shanxi Medical University Li Yan First Hospital of Shanxi Medical University Wenqu Yang Shanxi Datong University Hui Zhang First Hospital of Shanxi Medical University Junhong Guo ( [email protected] ) First Hospital of Shanxi Medical University Research Keywords: mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS), skeletal muscle, proteomics, DIA Posted Date: July 2nd, 2020 DOI: https://doi.org/10.21203/rs.3.rs-38357/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/25 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 denitive 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 identied 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 signicant 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 signicant 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 proling and bioinformatics analysis could contribute novel molecular networks to the pathogenesis of MELAS in a comprehensive manner. 1. Introduction The mitochondrial diseases are one of the most common congenital metabolic defects, with a minimum prevalence of 1:50001, 2. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS) is one of the relatively common mitochondrial diseases affecting the central nervous system. MELAS can affect multiple systems, with a wide range of clinical manifestations including stroke, recurrent headaches, epilepsy, hearing impairment, myopathy, dementia, ataxia and diabetes3. Almost 80% of MELAS patients are caused by the m.3243A > G mutation in the MT-TL1 gene4, 5. The mutation disturbs mitochondrial protein synthesis and ultimately affect the assembly of Complexes I, III and IV on oxidative respiration chains6. The molecular mechanism underlying the pathogenesis of MELAS is not fully understood. Finding out more Page 2/25 effective diagnostic methods, and fully understanding the pathogenesis at molecular level, can prevent and reduce the complications of MELAS in a more effective manner. Mitochondrial proteome is co-encoded by mtDNA and nuclear genome. The mtDNA only encodes 13 OXPHOS proteins; the nuclear genome encodes the remaining roughly 1500 protein and these proteins are transferred to the mitochondria through complex import systems7. The mutations of mitochondrial diseases affect proteins with undetermined functions. These proteins might shed light on the pathogenesis of mitochondrial diseases. Finding these proteins could help us gain valuable insight into pathophysiology of mitochondrial diseases. Recently, the combination of high-throughput omics techniques and complex bioinformatics analysis have brought new hope for revealing the pathogenesis and therapeutic targets about mitochondrial diseases. Increasingly, the quantitative proteomics and bioinformatics analysis can improve our understanding to the role of post-translational modications8. Compared to data-dependent-acquisition (DDA) method, the use of data-independent acquisition (DIA) method can obtain more reliable results and require a smaller samples size. So, the DDA-based proteomics is gradually replaced by DIA-based proteomics. In recent years, as a new tool, DIA-based proteomics is increasingly applied to the study of various diseases9. In this study, we performed nanospray liquid chromatography-mass spectrometry (LC-MS) based proteomic analysis in the DIA modes on skeletal muscle specimens from patients with MELAS. The purpose of this study was to reveal the differentially expressed proteins in skeletal muscle tissue. Subsequently, we performed bioinformatics analysis for potential signaling pathways in the hope of gaining a better understanding of the pathogenesis. 2. Materials And Methods 2.1 Characteristics of individuals and muscle biopsy The diagnostic criteria of MELAS study committee in Japan were adopted in this study10. Page 3/25 Category A: Clinical ndings of stroke-like episodes 1. headache with vomiting 2. seizure 3. hemiplegia 4. cortical blindness or hemianopsia 5. acute focal lesion observed via brain imaging Category B: evidence of mitochondrial dysfunction including 1. high lactate levels (2 mmol/L or more) in plasma and/or cerebral spinal uid or deciency of mitochondrial-related enzyme activities 2. mitochondrial abnormalities in muscle biopsy 3. denitive gene mutation related to MELAS Denitive MELAS two items of Category A and two items of Category B (four items or more). Suspicion of MELAS one item of Category A and two items of Category B (at least three items). In this study, all subjects underwent muscle biopsy for diagnostic purposes. We selected the MELAS patients positive point mutation for m.3243 A > G in genetic screening. We selected the age- and gender-matched subjects who were ultimately deemed to be free of neuromuscular diseases through muscle biopsies as controls. All collecting samples of muscle biopsies were informed consent of patients and controls. All procedures were approved by the Ethics committee of First Hospital of Shanxi Medical University (Taiyuan, China) and carried out in accordance with the principles of Helsinki Declaration. 2.2 Mitochondrial sequencing analysis The entire mitochondrial genome was isolated and mitochondrial m.3243A > G mutation was detected by next- generation sequencing (NGS). Briey, DNA was isolated from 200 mg muscle tissue by use of a DNA Kit CWE9600 (Beijing ComWin Biotech Co., Ltd), and mtDNA was amplied by long-range PCR using specic primer. Next-generation sequencing libraries were constructed by KAPA LTP Library Preparation Kit (KK8234, VWR, USA), and amplied libraries were used in Illumina NovaSeq High-throughput sequencing system (Illumina, USA). Sequenced data was assessed to be qualied by Sequencing Control Software (Illumina, USA) and analyzed by bioinformatic analysis referring human mitochondrial genome database. Mitochondrial m.3243A > G mutation was later conrmed by Sanger Sequencing using specic DNA primers anking MT-TL1 gene. 2.3 Protein Digestion 100 µg of protein from each sample was solubilized in a new Eppendorf tube containing 8 M urea to achieve a nal volume of 100 µL. Then, 2 µL of 0.5 M TCEP was added for incubation for 1 h at 37℃. After 40 minutes of incubation with 4 µL of 1 M iodoacetamide in the dark at room temperature, samples were then precipitated Page 4/25 by addition of -20℃ pre-chilled acetone at the ration of 1:5 at -20℃ overnight and centrifuged for 20 min at 12,000 G. Precipitates were washed and centrifuged again treated with 1 mL pre-chilled 90% acetone aqueous solution. Samples were re-dissolved in 100µL 100 mM TEAB and digested by Sequence grade modied trypsin (Promega, Madison, WI) containing 1:50 enzyme : protein (weight : weight) at 37℃ overnight. The peptide mixture was desalted by C18 ZipTip followed by quantication with Pierce™ Quantitative Colorimetric Peptide Assay (23275). SpeedVac was used for lyophilization. 2.4 Establish Spectrum Database 2.4.1 High PH reverse phase separation The mixed peptides were re-dissolved in buffer A (buffer A: 20 mM ammonium formate in water, pH 10.0, adjusted with ammonium hydroxide) and then loaded onto a reverse phase column (XBridge C18 column, 4.6 mm x 250 mm, 5 µm, Waters Corporation, MA, USA) using Ultimate 3000 HPLC system (Thermo Fisher scientic, MA, USA). High pH separation was achieved in 40 min with a linear gradient starting from 5% B to 45% B (B: 20 mM ammonium formate in 80% ACN, pH 10.0, adjusted with ammonium hydroxide). The column was re-equilibrated at 30℃ for 15 min (ow rate: 1 mL/min). A total of 10 fractions were obtained and dried by vacuum concentrator for future use. 2.4.2 nano-HPLC-MS/MS Analysis The peptides were re-dissolved in solvent A (A: 0.1% formic acid in water) and on-line nanospray LC-MS/MS was performed for analysis
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