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Principal Investigator: Yidong Bai
Organization: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
Fiscal Year: 2022
Award: $193,750
Funding agency: National Institute of Allergy and Infectious Diseases
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.
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