Results from the study, “CFTR-PTEN–dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection,” were published in the journal Science Translational Medicine.
CF is a genetic disorder caused by mutations in the CFTR gene, which provides instructions to make the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This protein works as a channel that transports molecules, such as chloride and water, in and out of cells.
Besides working as a channel, CFTR also interacts with other proteins, helping them to make complexes or reaching specific locations within a cell. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is one of these proteins.
PTEN is a tumor suppressor that is known to play a major role in controlling cell proliferation and metabolism. In normal conditions, PTEN interacts with CFTR at the membrane of mitochondria — the cell compartments responsible for producing energy — where it helps regulate mitochondria function.
However, in CF patients carrying genetic mutations that affect the structure and function of the CFTR protein, the CFTR-PTEN complex does not work properly.
In the study, researchers from the Columbia University Vagelos College of Physicians and Surgeons, New York, discovered that the dysfunction of both CFTR and PTEN causes a defect in mitochondria metabolism, leading to the excessive production of reactive oxygen species (ROS) and succinate in cells from the lungs.
ROS are toxic byproducts of a cell’s normal metabolism that must be broken down regularly to avoid oxidative stress (cellular damage that occurs as a consequence of high levels of oxidant molecules). For that reason, the buildup of ROS inside cells can be, by itself, a major problem.
Succinate, another byproduct of cellular metabolism, is a compound that certain bacteria can use as fuel to survive and multiply. These include Pseudomonas aeruginosa, a bacteria highly resistant to antibiotics that often causes lung infections in CF patients.
In the study, investigators found that the excesses of succinate stimulates the growth of P. aeruginosa in the lungs of mice with CF, but had no effect in the proliferation of Staphylococcus aureus, another bacteria that tends to invade the lungs and cause serious infections.
Moreover, researchers found that when P. aeruginosa bacteria have access to succinate, they produce great amounts of sticky slime, which makes them even more difficult to eliminate. On top of that, these succinate-fed bacteria also are capable of shutting down the host’s immune system, further hampering the body’s ability to fight the infection.
“Succinate-adapted bacteria divert their metabolism into the production of extracellular slime that makes the organisms extremely difficult to eradicate from the lung,” Alice Prince, MD, professor of pediatrics and senior author of the study, said in a press release. “These bacteria are the cause of chronic infection in cystic fibrosis.”
However, based on study findings made in mice models and human cells cultured in a lab dish, the researchers believe it may be possible to control lung infections caused by P. aeruginosa by finding a way to restore the function of the CFTR-PTEN complex.
For instance, the lumacaftor and ivacaftor combination therapy (sold under the brand name Orkambi by Vertex Pharmaceuticals) that is intended to restore the activity of CFTR in patients carrying certain mutations, has been shown to restore the activity of the CFTR-PTEN complex. It may have potential to lower the production of succinate in the lungs.
In addition, reducing the buildup of succinate in the lungs might be another mechanism that can be exploited to keep bacterial growth in check. This may be accomplished by controlling the body’s inflammatory response, since immune cells that infiltrate the lungs also contribute to the production of succinate.
“We predict that by controlling the exaggerated inflammation observed in the airway, we could reduce succinate and P. aeruginosa infection,” said Sebastián A. Riquelme, PhD, postdoctoral fellow in the department of pediatrics and lead author of the study.
“Preventing infection by P. aeruginosa could greatly improve the health of people with cystic fibrosis,” Riquelme said.
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