SARS-CoV-2 Causes Mitochondrial Dysfunction and Mitophagy Impairment

Abstract

Mitochondria, which is essential for adequate innate immune response, energy metabolism and mitochondria reactive oxygen species (ROS) production, might be in the cross fire of Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and host cell defense. However, little is known about interactions between mitochondria and SARS-CoV-2. We performed fluorescent microscopy and found an enrichment of SARS-CoV-2 replication products double stranded RNA (dsRNA) within mitochondria. The entry process of dsRNA might be mediated by Tom20 as observed by reduced mitochondrial localization of SARS-CoV-2 dsRNA in Tom20 knockdown cells. Importantly, decreased mitochondrial localization of dsRNA, as well as mitochondrial membrane stabilizers mdivi-1 and cyclosporin A, inhibited viral load in cells. Next, we detected mitochondrial dysfunction caused by SARS-CoV-2 infection, including mitochondrial membrane depolarization, mitochondrial permeability transition pore opening and increased ROS release. In response to mitochondrial damage, we observed an increase in expression and mitochondrial accumulation of Pink1 and Parkin proteins, as well as Pink-1-mediated recruitment of P62 to mitochondria, suggesting initiated mitophagy for mitochondrial quality control and virus clearance. Nevertheless, we observed that mitophagy was inhibited and stayed in early stage with an unchanged Hsp60 expression post SARS-CoV-2 infection. This might be one of the anti-autophagy strategies of SARS-CoV-2 and we used co-immunoprecipitation to found that SARS-CoV-2 infection inhibited P62 and LC3 binding which plays a critical role in selective envelopment of substrates into autophagosomes. Our results suggest that mitochondria are closely involved in SARS-CoV-2 replication and mitochondrial homeostasis is disrupted by SARS-CoV-2 in the virus-cell confrontation.

Exploring Mitochondrial Localization of SARS-CoV-2 RNA by Padlock Assay: A Pilot Study in Human Placenta

“…Recently, an innovative biochemical approach showed a physical and functional interaction between SARS-CoV-2 and host mitochondria [12]. These findings were also supported by imaging approaches using SARS-CoV-2-infected cells [13]. However, the absence of images visualizing the interaction between SARS-CoV-2 and mitochondria in tissues from patients with COVID-19 remains a critical gap.…”

Could SARS-CoV-2 Have Bacteriophage Behavior or Induce the Activity of Other Bacteriophages?

“…A negative control was obtained by omitting the primary antibody and using only the secondary gold-conjugate antibody. The control of immunogenicity of antibodies primary versus nucleocapsid protein of SARS-CoV-2 was assumed from Shang C. et al [ 14 ].…”

Human Cell Organelles in SARS-CoV-2 Infection: An Up-to-Date Overview

“…They also showed that the virus can disrupt the binding of the LIR domain of P62 protein with LC3 protein. This lowers the cell’s ability to ubiquitinate seized mitochondria, which blocks mitophagy, resulting in disrupted mitochondrial homeostasis and lowered viral RNA degradation [ 218 ].…”