Maria Fernanda Ziegler | FAPESP Agency – International study published in Science Translational Medicine reveals that the COVID-19 virus can impair the function of mitochondria in various tissues of the body – the cells' energy “power plant” –, creating a global and prolonged effect on all organs of the infected person.
The discovery of a systemic effect related to the inhibition of mitochondrial function paves the way for the search for new treatments both for severe cases of the disease and for patients with long COVID.
“The mitochondrial dysfunction caused by SARS-CoV-2 remains preserved, even when the virus is eliminated. This constitutes yet another systemic effect of the disease. In this work, we verified that the process occurs in various tissues of the body, not just in the cells of the immune system. [monócitos] or just in the lung, as initially imagined. Mitochondrial dysfunction can occur throughout the body and, among the consequences, is an increase in the inflammatory response in critically ill patients”, he explains. Pedro Moraes-Vieira professor at the Institute of Biology at the State University of Campinas (IB-Unicamp).
The research that gave rise to the article was developed within the scope of the COVID-19 International Research Team consortium, which brings together researchers from different centers in the United States, South Korea, Denmark, Paraguay and Brazil. The work is mainly financed by the National Institutes of Health (NIH, United States). This specific study is the continuation of an investigation started in 2020, with support from FAPESP, in which the Unicamp team, led by Moraes-Vieira, discovered that COVID-19 could generate dysfunction in the mitochondria. However, it was not yet proven that this was a widespread problem ( Read more at: agencia.fapesp.br/33237/
Stolen energy
In the most recent article, researchers analyzed infection by the virus that causes COVID-19 in two animal models (hamsters and mice). In addition, they examined data from more than 700 nasopharyngeal samples (from healthy people and patients with early-stage SARS-CoV-2 infection) and 35 tissue samples obtained through autopsy (from individuals with advanced-stage infection). – all collected during the pandemic in New York City.
The analyzes revealed that the virus suppresses the expression of certain mitochondrial genes (it is worth remembering that this organelle has its own genetic material, mitochondrial DNA). This process affects biochemical pathways, cellular energy production and activation of the immune response. This causes the cell to begin using an alternative route for energy production, called glycolysis, which consists of the breakdown of the glucose molecule into two pyruvic acid molecules, which then serve as an energy source for the virus. This way, it is able to replicate more, triggering a more exacerbated inflammatory response, that is, the severe form of COVID-19.
But the systemic effect of inhibiting mitochondrial function does not stop there. “We observed that even when the virus was eliminated from the body and the inhibition of mitochondrial genes in the lung had ceased, the expression of these mitochondrial genes in the heart, kidney, liver or lymph nodes remained impaired, potentially leading to severe COVID-19 pathology. . We also believe that this inhibition of mitochondrial genes may be related to the so-called long COVID when there is no longer any virus. The patient is cured of the disease, but some symptoms and sequelae persist”, comments Moraes-Vieira, who is also a researcher at the Experimental Medicine Research Cluster (EMRC) and the Center for Research on Obesity and Comorbidities OCRC ), a FAPESP Research, Innovation and Dissemination Center (CEPID) at Unicamp.
As the researcher recalls, experiments carried out on infected monocytes by the Unicamp group in 2020 showed that the suppression of mitochondrial genes almost inactivated the oxidative phosphorylation process, which uses the energy released by the oxidation of nutrients to produce the molecule known as triphosphate of adenosine, or ATP, which serves as “fuel” for cells.
“This creates the need to look for new ways to produce energy, which, in relation to the symptoms of the disease, can manifest itself in the form of shortness of breath and tiredness, for example,” he says. This data was published in 2020 by the Moraes-Vieira group.
The nasopharyngeal and tissue samples analyzed in the now published study showed that the suppression of genes and mitochondrial function was occurring in different organs, such as the heart, liver, kidneys and lymph nodes.
“Even after the virus was eliminated, the inhibition of genes related to oxidative phosphorylation remained. It seems to be an irreversible situation if we think about cases of long COVID. This paves the way to seek new treatments that involve restoring mitochondrial function. And it is precisely on this point that we will focus on the next studies”, he comments.
The study Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts can be read at: www.science.org/doi/10.1126/scitranslmed.abq1533#con45