Mitochondrial DNA Triggers Inflammation in Sickle Cell Anemia Patients

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Sickle cell anemia
[Source: Dr_Microbe/Getty Images]

Free floating mitochondrial DNA fragments in the blood are a trigger for inflammation in people with sickle cell disease, suggests research carried out at the NIH’s National Heart, Lung, and Blood Institute in Bethesda.

The team discovered that the red blood cells of people with this chronic condition seem to accumulate mitochondria, which are absent from healthy blood cells. When these organelles break up their DNA is also broken up and found circulating in the blood of people with sickle cell disease.

The researchers found that the circulating mitochondrial DNA they found in the blood of these patients had abnormally low levels of methylation. They think this could be linked to the excessive inflammation these fragments seem to cause.

“These study findings suggest that measuring DNA of mitochondrial origin could help us better understand its role in pain crises, destruction of red blood cells, and other inflammatory events in sickle cell disease,” said Swee Lay Thein, M.B., D.Sc., chief of the Sickle Cell Branch at the National Heart, Lung, and Blood Institute, who led the research.

“It could also serve as a marker of disease progression and a way to measure the effectiveness of therapeutic interventions.”

Thein and colleagues carried out an in-depth analysis of DNA and DNA fragments extracted from the blood plasma of 34 people with sickle cell anemia, as well as from eight healthy volunteers. This study is published in the journal Blood.

Mitochondria are present in and provide energy for a wide range of cells, but in healthy blood, red blood cells do not normally keep their mitochondria as they mature as they do not require them. The researchers found this was not the case in red blood cells from sickle cell patients, which have an abnormal ‘sickle’ shape.

“We were intrigued when we found higher levels of free-floating mitochondrial DNA in the plasma of the patients with sickle cell disease,” Thein said. “These were shorter and more fragmented than free-floating nuclear DNA fragments, which are also known to drift in the patient’s blood.”

Another key feature of these fragments was their methylation status. They had very low levels of methylation, which can impact gene expression. Notably, in a small group of patients who had samples taken during a flare up of their condition the methylation level was even lower.

Thein and team found that the mitochondrial fragments triggered the formation of neutrophil extracellular traps (NET) – the formation of tiny fibers made of DNA from neutrophils that trap pathogens and form the bodies first line of defense against infection. As with any immune response to supposed infection, this also triggers inflammation.

In this case, the team believes this initial inflammatory response could trigger interferon gene expression in something called the cGAS-STING pathway and lead to longer term, more chronic inflammation, as seen in patients with sickle cell disease.

The research team are now looking at therapeutic options linked to their findings. For example, Thein and colleagues were able to block NET formation using a small molecule inhibitor and want to explore other possible drug candidates that could block this type of inflammation.

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