Characterization the disruption of mitochondrial function and induction of oxidative stress by SARS-CoV2

SARS-CoV2 对线粒体功能的破坏和氧化应激诱导的表征

• 批准号: 10640165
• 负责人: Yidong Bai
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-08 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10640165
• 关键词: 2019-nCoV; A549; ACE2; ATP Synthesis Pathway; Affect; Aging; Antioxidants; Binding; Biogenesis; Biology; COVID-19; COVID-19 impact; COVID-19 pathogenesis; COVID-19 patient; COVID-19 test; COVID-19 treatment; Cell Death; Cell Line; Cell model; Cells; Compensation; Complex; Defect; Disease; Elderly; Electron Transport; Energy Metabolism; Engineering; Epithelial Cells; Etiology; Exhibits; Fatigue; Gene Expression; Genes; Genome; Hospitalization; Human; Hypoxia; Immune response; Invaded; Investigation; Knowledge; Laboratories; Lactate Dehydrogenase; Lead; Leber' s Hereditary Optic Neuropathy; Lentivirus; Malignant Neoplasms; Measures; Mediating; Medicine; Metabolic; Metabolic Diseases; Metabolic syndrome; Minority Groups; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Mitochondrial Proteins; Modeling; Molecular Target; Mutation; NADH dehydrogenase (ubiquinone); Neurodegenerative Disorders; Nuclear; Nuclear Import; Organ; Oxidative Phosphorylation; Oxidative Stress; Oxidative Stress Induction; Pathogenicity; Patients; Peptides; Phosphorylation; Population; Process; Production; Protein Biosynthesis; Proteins; Proteomics; Protons; Public Health; Reactive Oxygen Species; Reporting; Research; Resistance; Respiration Disorders; Respiratory Chain; Rest; SARS-CoV-2 genome; SARS-CoV-2 infection; Series; Serum; Shortness of Breath; Symptoms; Syndrome; System; Testing; Time; Translations; Viral Proteins; Virus; Virus Replication; Yeasts; aging population; alveolar epithelium; common symptom; effective therapy; experimental study; high risk; inducible gene expression; innovation; insight; mitochondrial DNA mutation; mitochondrial dysfunction; mutant; novel; novel strategies; oligomycin sensitivity-conferring protein; oxidative damage; premature; protein complex; respiratory; respiratory protein; stable cell line; systematic review

1 Populations at higher risk of severe disease from COVID-19 are the elderly and those with metabolic 2 syndromes, the populations known for compromised mitochondrial function. In addition, the most common 3 symptoms in hospitalized COVID patients are shortness of breath and fatigue, indicating deficient oxygen and 4 energy metabolism, also suggesting defective mitochondria. COVID-19 patients also have significantly 5 elevated serum lactate dehydrogenase and increases oxidative stress, pointing to a possibility of reduced 6 mitochondrial oxidative phosphorylation (OXPHOS). Together, these information leads us to consider whether 7 mitochondrial dysfunction might contribute to the pathogenesis of COVID-19. A comprehensive proteomics 8 investigation and other studies identified at least 6 mitochondrially-localized SARS-CoV-2 viral proteins which 9 were shown to interact with host cell mitochondrial proteins involved in critical OXPHOS pathways converging 10 on respiratory Complex I biogenesis. Our lab has established expertise on the investigation of mitochondrial 11 biology and mitochondrial medicine, especially on Complex I-related OXPHOS biogenesis. Over the years we 12 have developed a series of unique cell models with different types of complex I defects, including sets of cells 13 with different contents of functional complex I subunits, a set cells with different complex I assembly capacity, 14 and a set of cells carrying pathogenic mutations in complex I subunit genes, as well as an engineered system 15 to rescue complex I-related function with the introduction of a yeast Complex I counterpart NDI1 gene. These 16 models exhibit different levels of complex I subunit expression, different capacities of complex I and overall 17 respiratory machinery assembly, and different complex I and overall mitochondrial OXPHOS activities. 18 Accordingly, these cell models also exhibit different sensitivities to oxidative stress and cell death. We have 19 also initiated a line of study on the effect of viruses on mitochondria and consequent implications on human 20 diseases. In addition, we have achieved to obtain 1.Inducible expression which could turn on and off the 21 SARS-CoV-2 proteins in our cell models at proper levels; 2.Multiple genes expression which can express 22 multiple SARS-CoV-2 proteins targeting one or multiple OXPHOS pathways simultaneously in our cell models; 23 3.Establishment of A549-hACE2 cell, where a human alveolar epithelial cell line, A549 was transduced with 24 lentiviruses expressing human ACE2. A549-hACE2 cells readily support SARS-CoV2 infection and replication; 25 4.Generated mutant SARS-CoV2 lines which could serve as controls. These provide a unique opportunity for 26 us to utilize our unique systems and expertise to fulfill with two independent and integrated aims to study the 27 interactions between SARS-CoV2 and mitochondria, and their implications on oxidative stress and cell death, 28 both in cell models with regulated mitochondrial function and in human alveolar epithelial cell line infected with 29 SARS-CoV2. We expect these research will help identify molecular targets of SARS-CoV2 proteins in host 30 cells and will also provide novel approaches for protecting against the harmful effects of COVID-19. 31 32

1 .老年人和代谢性疾病患者是COVID-19重症风险较高的人群