A multi-institutional consortium of researchers led by a team at Children’s Hospital of Philadelphia (CHOP) and the COVID-19 International Research Team (COV-IRT) has found that the genes of the mitochondria, the energy producers of our cells, can be negatively impacted by the virus, leading to dysfunction in multiple organs beyond the lungs.
Mitochondria are found in every cell in our bodies. The genes responsible for generating mitochondria are dispersed across both the nuclear DNA located in the nucleus of our cells and the mitochondrial DNA (mtDNA) located within each mitochondrion. Prior studies have shown that SARS-CoV-2 proteins can bind to mitochondrial proteins in host cells, potentially leading to mitochondrial dysfunction.
To understand how SARS-CoV-2 impacts mitochondria, researchers wanted to analyze mitochondrial gene expression to detect differences caused by the virus. To do this, they analyzed a combination of nasopharyngeal and autopsy tissues from affected patients and animal models.
The study found that in autopsy tissue, mitochondrial gene expression had recovered in the lungs, but mitochondrial function remained suppressed in the heart as well as the kidneys and liver. When studying animal models and measuring the time when the viral load was at its peak in the lungs, mitochondrial gene expression was suppressed in the cerebellum even though no SARS-CoV-2 was observed in the brain. Additional animal models revealed that during the mid-phase of SARS-CoV-2 infection, mitochondrial function in the lungs was beginning to recover.
Taken together, these results reveal that host cells respond to initial infection in a way that involves the lungs, but over time, mitochondrial function in the lungs is restored, while in other organs, particularly the heart, mitochondrial function remains impaired.
“This study provides us with strong evidence that we need to stop looking at COVID-19 as strictly an upper respiratory disease and start viewing it as a systemic disorder that impacts multiple organs,” said co-senior author Douglas C. Wallace, PhD.
While future studies using this data will study how systemic immune and inflammatory responses may be responsible for more severe disease in some patients, the research team did find a potential therapeutic target in microRNA 2392 (miR-2392), which was shown to regulate mitochondrial function in human tissue samples used in this study.
“This microRNA was upregulated in the blood of patients infected by SARS-CoV-2, which is not something we normally would expect to see,” said co-senior author Afshin Beheshti, PhD. “Neutralizing this microRNA might be able to impede the replication of the virus, providing an additional therapeutic option for patients who are at risk for more serious complications related to the disease.”
Joseph W. Guarnieri, Joseph M. Dybas, Hossein Fazelinia, Man S. Kim, Justin Frere, Yuanchao Zhang, Yentli Soto Albrecht, Deborah G. Murdock, Alessia Angelin, Larry N. Singh, Scott L. Weiss, Sonja M. Best, Marie T. Lott, Shiping Zhang, Henry Cope, Victoria Zaksas, Amanda Saravia-Butler, Cem Meydan, Jonathan Foox, Christopher Mozsary, Yaron Bram, Yared Kidane, Waldemar Priebe, Mark R. Emmett, Robert Meller, Sam Demharter, Valdemar Stentoft-Hansen, Marco Salvatore, Diego Galeano, Francisco J. Enguita, Peter Grabham, Nidia S. Trovao, Urminder Singh, Jeffrey Haltom, Mark T. Heise, Nathaniel J. Moorman, Victoria K. Baxter, Emily A. Madden, Sharon A. Taft-Benz, Elizabeth J. Anderson, Wes A. Sanders, Rebekah J. Dickmander, Stephen B. Baylin, Eve Syrkin Wurtele, Pedro M. Moraes-Vieira, Deanne Taylor, Christopher E. Mason, Jonathan C. Schisler, Robert E. Schwartz, Afshin Beheshti, Douglas C. Wallace. Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts. Science Translational Medicine, 2023; 15 (708) DOI: 10.1126/scitranslmed.abq1533
Children’s Hospital of Philadelphia. “COVID-19 causes mitochondrial dysfunction in heart and other organs, researchers find.” ScienceDaily. ScienceDaily, 10 August 2023. <www.sciencedaily.com/releases/2023/08/230810180123.htm>.
Photo by Renaldo Matamoro