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

• Published in: Communications biology Vol. 5; no. 1; pp. 1 - 15
• 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: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 13/89; 14/10; 14/19; 45/91; 631/80/221; 631/80/304; 64/24; 64/60; 82/58; 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
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03986-6

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.