Experts Target Mitochondrial Dysfunction After Pediatric TBI

Jul 6 2015

Experts Target Mitochondrial Dysfunction After Pediatric TBI

TBIPediatric traumatic brain injury (TBI) will become a major cause of death and disability of children within the next several years, The World Health Organization predicts, as many third-world countries become urbanized. Whether the injuries result from motor vehicle crashes on the road or sports collisions on the field, researchers have shown that all cases of TBI can be serious concerns.

A TBI is caused by a bump, blow, or jolt to the head or a penetrating head injury. The majority of TBIs that occur each year are concussions or other forms of mild TBI. Some concussion symptoms may appear immediately after the injury, while others may not show up for several days. They can include headache, nausea, dizziness, sleep problems, difficulty concentrating, and moodiness.

Todd Kilbaugh, MD, an anesthesiologist and intensivist with the Department of Anesthesiology and Critical Care Medicine at The Children’s Hospital of Philadelphia; colleagues from Lund University, Sweden; and senior collaborator Susan Margulies, PhD, from the Department of Bioengineering at the University of Pennsylvania, have developed comprehensive large animal models of pediatric TBI. The study team reported in two recent publications that ongoing injury persisted at a submolecular level 24 hours after a mild to moderate brain injury occurred.

The investigators hypothesize that alterations in mitochondrial function could interfere with the brain’s ability to limit damage, which is called neurodegeneration, and heal itself, which is called neuroregeneration, leading to long-term inflammation and problems with the way the brain affects emotion, behavior, and learning. Mitochondria are organelles that are essential to the production of the body’s energy supply and also regulate a cells’ essential, everyday housekeeping.

“Even in critical illness, not just traumatic brain injury, we believe that these little organelles can act like a light switch that controls whether a cell lives or dies,” Dr. Kilbaugh said.

The researchers used sophisticated technology called high-resolution respirometry to analyze minute tissue samples. They measured the amount of oxygen the tissue was using to pinpoint the real-time activity of mitochondrial machinery called the electron transport system.

“For the first time, this gave us a window into how the brain responds to the energetic crisis that it goes under in response to an injury,” Dr. Kilbaugh said. “We took apart each individual aspect of the electron transport system to figure out where things are working and where things are not working.”

By better understanding the bioenergetics failure that occurs within the mitochondria, the researchers aim to develop new pharmacologic approaches or interventions that can support the health and energy output of cells during a crisis. Finding novel ways to quickly help children who experience TBI could prevent a lifetime of medical care and related costs to society.

“Like an athlete who needs to exercise, run, and get stronger after an injury, there are likely parts of the brain and mitochondria that we can improve after injuries to produce more energy in the brain to help with recovery and healing processes,” said Dr. Kilbaugh, who also is an assistant professor of Anesthesiology and Critical Care at the Hospital of the University of Pennsylvania.

Results of the studies appeared in the journals Experimental Neurology and PLoS One. Dr. Margulies, who leads the Injury Biomechanics Lab at the University of Pennsylvania, is the senior author.