Building on recent findings that show how the SARS-CoV-2 virus affects mitochondrial function in various parts of the body, researchers have discovered that using antioxidants targeted at mitochondria could help lessen the impact of the virus without leading to resistance from gene mutations, a tactic that could potentially be applied to treat other viruses.
Expanding on previous research illustrating how the SARS-CoV-2 virus disrupts mitochondrial function in several areas of the body, scientists from Children’s Hospital of Philadelphia (CHOP) have found that mitochondria-targeted antioxidants can mitigate the virus’s effects without triggering resistance from viral gene mutations. These findings were recently published in the journal Proceedings of the National Academy of Sciences.
In the past year, a team of researchers from multiple institutions revealed that the genes of mitochondria, which are responsible for producing energy in our cells, can be harmed by the virus. This damage can lead to dysfunction in various organs beyond just the lungs. The proteins from SARS-CoV-2 can attach to mitochondrial proteins in host cells and suppress the expression of mitochondrial genes. Although the virus primarily attacks the lungs at first, it can also affect other organs, particularly the heart. Even if the lungs recover, the heart and other visceral organs may continue to experience suppressed mitochondrial function.
During a SARS-COV-2 infection, mitochondrial oxidative phosphorylation (OXPHOS), the primary process through which mitochondria create energy for cells, gets disrupted. This disruption leads to an increase in mitochondrial reactive oxygen species (mROS), which then triggers hypoxia-inducible factor-1alpha (HIF-1α). This results in a shift from burning carbohydrates and fats through OXPHOS for energy production to glycolysis, which provides materials for viral replication. The elevated mROS also damages mitochondrial DNA (mtDNA), which is released into the cytosol to activate inflammatory responses, affecting the organs as a result.
“We believed that by reducing the amount of mROS, we could potentially impede SARS-CoV-2 from causing illness, thus interrupting the metabolic shift crucial for viral replication,” said the study’s lead author Joseph W. Guarnieri, PhD, a postdoctoral fellow at the Wallace lab at the Center for Mitochondrial and Epigenomic Medicine (CMEM) at CHOP. “Since the virus relies on mROS as a key signal to trigger the transition from energy production to viral material production, our next aim was to investigate whether inhibiting mROS production could hinder viral replication and disease progression.”
To examine this theory, researchers used a mouse model that expressed the human ACE2 gene, which allows the virus to infect cells. When these mice were treated with an antioxidant enzyme, specifically mitochondria-targeted catalase or the mitochondria-targeted catalytic antioxidant compound EUK8, the negative effects of the viral infection, such as weight loss, disease severity, levels of circulating mtDNA, were all reduced. This coincided with an increase in lung OXPHOS, along with reduced levels of HIF-1α, viral proteins, and inflammatory molecules in the lungs.
“We believe that reducing mROS could be a superior approach to lessening the harmful effects of SARS-CoV-2,” explained senior author of the study, Douglas C. Wallace, PhD, who is also the director of the CMEM at CHOP. “The virus continually mutates its ‘S’ protein gene to evade the immunity created by current anti-S vaccines. By adjusting cmROS levels, we are creating an unfavorable environment in the host cell for the virus to complete its life cycle, something the virus cannot easily adapt to.”
This study received support from the Department of Defense W81XWH-21-1-0128 grant PR202887 and The Bill and Melinda Gates Foundation grant INV-04672. Additional funding came from the National Institutes of Health grants 1R01CA259635, 1R01AG078814, and R01NS114656, as well as the Foerderer grant 00003469.
