Severe COVID-19 arises in part from the SARS-CoV-2 virus’s impact on mitochondria, tiny oxygen-burning power plants in cells, which can help trigger a cascade of organ- and immune system-damaging events, suggests a study by investigators at Weill Cornell Medicine, Johns Hopkins Medicine, Children’s Hospital of Philadelphia, and the University of Pittsburgh, along with other members of the COVID-19 International Research Team.

Severe COVID-19 has been considered an inflammatory “cytokine storm” condition in which the immune response to a viral infection becomes excessive, flooding the bloodstream and tissues with immune signaling proteins at levels that cause lung-impairing inflammation and other signs and symptoms.

The new study, published Nov. 27 in Proceedings of the National Academy of Sciences, extends the scientific understanding of the molecular pathways driving this storm. By using RNA sequencing and other laboratory techniques on patient and animal model tissue samples, the investigators were able to examine these processes in great detail. Weill Cornell Medicine researchers, led by Dr. Robert Schwartz, associate professor of medicine, provided much of the de-identified patient material, including nasopharyngeal swabs and autopsied organ samples, as well as COVID-19 animal models, and contributed to their analysis.

The teams’ findings show that SARS-CoV-2 virus infection can cause significant damage to mitochondria in infected cells – damage that activates the immune system, contributing to the storm of inflammatory and other responses.

Prominent among these responses, the researchers noted, is the overactivation of a blood-pressure-regulating system called the renin-angiotensin-activation-system (RAAS). The overactive RAAS is associated with abnormal blood clotting – a striking feature of severe COVID-19 – and, the researchers noted, with scarring-like abnormalities in lymph nodes, and dysfunctions of the immune cells found within them. The latter, the researchers say, may account for the impaired immune function that is also seen in severe COVID-19.

“One of the suggestions of these findings is that there is, early in the process, profound mitochondrial dysfunction and damage, which is then driving RAAS overactivation, which in turn contributes to the multi-organ damage of severe COVID-19,” said Schwartz, who is also a hepatologist at NewYork-Presbyterian/Weill Cornell Medical Center. “In addition, we’re concerned that these processes underlying acute COVID-19 may not always return to normal afterwards.” 

The researchers are currently investigating this possibility in cases of “long COVID,” a syndrome that features lingering inflammation as well as immune cell dysfunction.

The research reported in this story was supported in part by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Department of Defense.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Dr. Robert Schwartz.

Jim Schnabel is a freelance writer for Weill Cornell Medicine.