SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a respiratory pathogen leading to serious multi-organ damage. However, little is known about SARS-CoV-2-induced cellular alterations for understanding robust virus propagation yet. Here we report that SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics and activates epidermal growth factor receptor (EGFR)-mediated cell survival signal cascade for sustaining persistence of SARS-CoV-2. We found that SARS-CoV-2 causes increase in mitochondrial transmembrane potential by SARS-CoV-2 RNA-nucleocapsid cluster, thereby abnormally promoting mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) process followed by abundant ATP production. SARS-CoV-2 also activated EGFR signal cascade and subsequent mitochondrial EGFR accumulation which contributes to the maintenance of abnormal OXPHOS and viral propagation. Therapeutic options for the treatment of COVID-19 are still inadequate. The FDA-approved EGFR inhibitors caused a remarkable reduction in SARS-CoV-2 propagation. Among EGFR inhibitors, vandetanib showing the highest anti-SARS-CoV-2 efficacy exhibited the potent antiviral activity against various SARS-CoV-2 variants including B.1.1.7 (UK variant) and B.1.351 (SA variant) lineages in both in vitro cell culture and in vivo animal experiments using wild-type aged mouse susceptible to SARS-CoV-2 infection, suggesting that EGFR is an attractive host target for combatting COVID-19. Overall, our results suggest that SARS-CoV-2 induces aberrant mitochondrial dynamics and bioenergetics, which significantly contributes to robust SARS-CoV-2 propagation.

Infectious viruses and neurodegenerative diseases: The mitochondrial defect hypothesis

“…Although the effects of viruses in the pathogenesis of neurodegenerative diseases remain controversial, various studies suggest that they may be the initiating causative agent of neurodegenerative pathologies 104 . There is substantial evidence that viruses such as SARS‐COV, 105 HIV, and HCV impair mitochondria through pathways such as increasing mitochondrial oxidative stress 106 and disrupting mitochondrial mass homoeostasis 107 . Importantly, we found a close positive feedback link between these pathways during our study, for example, the increase of mitochondrial oxidative stress interferes with the normal expression of mitochondrial proteins such as Drp1, Fis1 and so on through p53 signalling pathway, and the inhibitory effect of Fis1 on mitochondrial fusion is weakened, which disrupts the equilibrium between mitochondrial fission and fusion, 108 and further generates ROS impairing mitochondrial turnover function 109 .…”

Targeting epidermal growth factor receptor signalling pathway: A promising therapeutic option for COVID‐19

“…The EGFR gene expression is also promoted at transcriptional levels upon SARS‐CoV‐2 infection, as it elevates mitochondrial bioenergetics and promotes the process of oxidative phosphorylation (OXPHOS) to induce robust virus propagation. Therefore, SARS‐CoV‐2‐induced EGFR activation and its accumulation on the outer membrane of mitochondria (OMM) are vital for sustaining the process of mitochondrial OXPHOS and SARS‐CoV‐2 propagation 53 …”

“…Therefore, SARS-CoV-2-induced EGFR activation and its accumulation on the outer membrane of mitochondria (OMM) are vital for sustaining the process of mitochondrial OXPHOS and SARS-CoV-2 propagation. 53 Furthermore, the NSP1 and ORF6 proteins of SARS-CoV-2 inhibit the signal transducer and activator of transcription 1 (STAT1) activity. 54 The loss of STAT1, together with lung injury, causes EGFR expression in the infected alveolar epithelial cells.…”