SARS-CoV-2 Nsp6 damages Drosophila heart and mouse cardiomyocytes through MGA/MAX complex-mediated increased glycolysis

SARS-CoV-2 infection causes COVID-19, a severe acute respiratory disease associated with cardiovascular complications including long-term outcomes. The presence of virus in cardiac tissue of patients with COVID-19 suggests this is a direct, rather than secondary, effect of infection. Here, by expres...

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Bibliographic Details
Published in:Communications biology 2022-09, Vol.5 (1), p.1-15, Article 1039
Main Authors: Zhu, Jun-yi, Wang, Guanglei, Huang, Xiaohu, Lee, Hangnoh, Lee, Jin-Gu, Yang, Penghua, van de Leemput, Joyce, Huang, Weiliang, Kane, Maureen A., Yang, Peixin, Han, Zhe
Format: Article
Language:English
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Biology
Biomedical and Life Sciences
Cardiomyocytes
Congestive heart failure
Coronaviruses
COVID-19
Drosophila
Glucose
Glycolysis
Heart failure
Insects
Life Sciences
Mitochondria
Myc protein
Pathology
Phenotypes
Reactive oxygen species
Respiratory diseases
Severe acute respiratory syndrome coronavirus 2
Transcriptomics
Viruses
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Summary:SARS-CoV-2 infection causes COVID-19, a severe acute respiratory disease associated with cardiovascular complications including long-term outcomes. The presence of virus in cardiac tissue of patients with COVID-19 suggests this is a direct, rather than secondary, effect of infection. Here, by expressing individual SARS-CoV-2 proteins in the Drosophila heart, we demonstrate interaction of virus Nsp6 with host proteins of the MGA/MAX complex (MGA, PCGF6 and TFDP1). Complementing transcriptomic data from the fly heart reveal that this interaction blocks the antagonistic MGA/MAX complex, which shifts the balance towards MYC/MAX and activates glycolysis—with similar findings in mouse cardiomyocytes. Further, the Nsp6 -induced glycolysis disrupts cardiac mitochondrial function, known to increase reactive oxygen species (ROS) in heart failure; this could explain COVID-19-associated cardiac pathology. Inhibiting the glycolysis pathway by 2-deoxy-D-glucose (2DG) treatment attenuates the Nsp6 -induced cardiac phenotype in flies and mice. These findings point to glycolysis as a potential pharmacological target for treating COVID-19-associated heart failure. SARS-CoV-2 protein expression studies in the Drosophila heart suggest a cause of COVID-19-associated cardiac pathology via interaction of virus Nsp6 with the host MGA/MAX complex disrupting glycolysis and cardiac mitochondrial function.
ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-022-03986-6