Scientists and clinicians studying COVID-19 have long suspected that the disease doesn’t just affect the lungs, but many other organ systems too. Now, researchers have identified a mechanism that could explain why and reveal new pathways to find treatments for long COVID.
In a study published Aug. 9 in Science, a team led by Children’s Hospital of Philadelphia (CHOP) and the COVID-19 International Research Team (COV-IRT) presented data from experiments on human tissue samples and animal models showing that SARS-CoV-2 suppresses the genes in mitochondria, a component of cells that generates the energy they need to function. The changes were found throughout the lungs, brain, heart, kidneys, liver and lymph nodes during the acute stages of infection, and in some organs remained even after the virus itself had been cleared.
“This is a very important study,” Eric Topol, M.D., a cardiologist at Scripps Research Institute who was not affiliated with the investigation, told Fierce Biotech Research in an interview. “We haven’t really understood how important the mitochondria might be for long COVID, and this study is really elegant.”
While this isn’t the first study to show that SARS-CoV-2 affects mitochondria, it is the first to show how the virus impacts their genes. Previous research had indicated that the virus’ presence is associated with a decline in oxidative phosphorylation, or OXPHOS, proteins, which drive energy-producing pathways in mitochondria. The new findings show that this is because the virus actively prevents OXPHOS genes from being transcribed.
“SARS-CoV-2 is causing a huge mitochondrial suppression, which would explain a lot of the symptoms you see—the brain fog, the fatigue, the cardiovascular issues,” Afshin Beheshti, Ph.D., senior author and president of COV-IRT, said in an interview. The brain and heart contain the most mitochondria of any of the body’s organs, he added.
While previous studies have focused on one organ system at a time, the new CHOP and COV-IRT work includes data from multiple systems throughout the body. In addition to rodent models, the researchers looked at gene transcription in nasopharyngeal samples from live patients as well as autopsy samples of the heart, kidney, liver, lungs and lymph nodes from 35 people who had died from severe COVID-19. The researchers also looked at different stages of infection.
“What we saw was that there were alterations [in the mitochondrial genes] all throughout the acute or early and the late and severe stages,” first author Joseph Guarnieri, Ph.D., a postdoctoral research fellow at CHOP, said in an interview.
Brain fog and mitochondrial suppression showed up in the hamsters in the early stages. Mitochondrial dysfunction declined in the heart, liver, kidney and lymph nodes in the middle and late stages when the virus had already been cleared from the body. And while the mitochondrial genes turned back on in the lungs over time, they remained suppressed in other organ systems, including the heart.
“That really indicates to us that complications associated with mitochondrial dysfunction early on can then contribute to long-term effects later and eventually into increased COVID severity due to complications,” Guarnieri said. “Our data really points to problems with the heart … one could hypothesize that even people who survive with slightly less severity might have long-term complications in some of these tissues if they don’t fully recover.”
Exactly how the virus exerts its mitochondrial-gene suppressing effects comes down to a sequence of non-coding RNA called microRNA 2392, or miR-2392. Beheshti’s team had previously shown that it was present in abnormally high levels in the blood and urine of patients with COVID-19, regardless of how severe their infection was. The new study shows that SARS-CoV-2 uses it to suppress mitochondrial genes.
Though the link between microRNA and viruses is still new, there’s evidence that COVID-19 isn’t the only disease that works this way. The hepatitis C virus, for instance, incorporates a stretch of host microRNA into its genome as a way to disguise it from the immune system. It then upregulates suppressive microRNA throughout the body to hold down gene transcription in the host’s mitochondria.
“It’s basically terraforming your body, in a sense, to allow the virus to survive—now it doesn’t have to deal with all these pesky immune factors to fight it off,” Beheshti explained. His team wasn’t aware of the findings on hepatitis C before they discovered in an earlier study that SARS-CoV-2 was doing the same thing, he said.
When his team ran analyses on what diseases that could arise from overexpression of miR-2392, they found many conditions that mapped onto the ones linked with COVID, Beheshti added. Some, like vision problems, have more recently come to light as potential symptoms of long COVID.
“They predicted some things that were already known at the time, like cardiovascular and CNS issues, but a lot of other things popped up like vision loss or hearing loss, too,” he recalled. “Now we know COVID can cause hearing issues and vision issues. All the different diseases that are linked to long COVID, this microRNA is associated with them too.”
The team has already identified some existing drugs that may be able to restore gene expression by boosting mitochondrial function, including the supplement N-acetyl cysteine, more commonly known as NAC, and the mTOR inhibitor rapamycin. Metformin, too—which has already shown efficacy in preventing long COVID in some patient cohorts—might also be exerting its protective effects this way, Topol noted.
“They’ve pinpointed parts of the pathway in the mitochondria where we know drugs work, so it’s a nice connection,” he said.
Directly targeting miR-2392 might be an option as well. In preliminary experiments on cells and in hamsters, a compound that suppresses miR-2392 was able to reduce SARS-CoV-2 replication, and thus the viral load. While using microRNA this way is still quite new, other companies are trying it for different viruses, and Beheshti's team could do the same with the right funding, he added.
In addition to seeing whether these treatments might prove therapeutic in animal models, they’re also using artificial intelligence to identify others, the researchers said. They’ll also follow up with more studies that probe how long mitochondrial dysfunction lasts, and whether these mechanisms really do explain long COVID.