A research team supported by the National Institutes of Health (NIH) has found that conditions known to cause nerve damage, or neuropathy, disrupt a crucial energy-transfer process between special support cells called satellite glial cells (SGCs) and the sensory neurons they surround. The investigators discovered that the energy producing machinery of cells, known as mitochondria, are transferred through tiny tubes that form between the SGCs and neurons. They found that this transfer became obstructed in animal models of chemotherapy and diabetes , while restoring it attenuated pain behavior and promoted nerve regeneration after nerve injury.
The results of this study highlight a new avenue for potential neuropathy treatments and provide insight into how some of the body's most energy-hungry cells are powered.
"Sensory neurons can run from near the spine all the way to the tips of your toes and fingers," said senior author of the study, Ru-Rong Ji, Ph.D., a professor of anesthesiology and neurobiology and Director of Center for Translational Pain Medicine, at Duke University School of Medicine, Durham, North Carolina. "When they fire, they carry signals a great distance, which is why these cells have a particularly high demand for energy."
While it has not been clear how these large cells manage to stay energized, Ji and his colleagues have suspected they may lean on a member of the peripheral nervous system's supporting cast. Satellite glial cells (SGCs), which are already known to provide nutrients, cushioning, and other kinds of support to sensory neurons, seemed like a prime candidate.
Prior research has shown that neural support cells are capable of swapping mitochondria with each other, but evidence that this occurs in living organisms has been limited.
For this new study, the authors sought to learn if this phenomenon might be at play between SGCs and the neurons they envelop within clusters of cells near the spine called dorsal root ganglia. To start, they grew mice cells of both types together in a dish and used a high-resolution imaging technique to catch a first glimpse of the supply chain in peripheral neural cells. Then, with a different type of microscopy, they visualized mitochondrial transfer inside tube-like structures in whole dorsal root ganglia from mice.
"The images are quite striking. You can even see bulges in the tubes between cells where the mitochondria are in transit," Ji said.
Through additional experiments, the team confirmed that mitochondria travel through these tunneling nanotubes, or TNTs, in living mice as well and showed that these tubes are necessary for regulating pain. The researchers also learned that SGCs were the primary initiators of tube formation, meaning mitochondrial transfer was mostly a one-way street, from SGCs to neurons.
The researchers delved deeper into the role of mitochondrial transfer by observing how the process in mice was affected by nerve injury. The team learned that smaller neurons were the first to lose mitochondria following injury; SGCs seemed to favor powering the larger cells, offering them more protection. The particular vulnerability of smaller neurons to energy loss might partially explain why damage to the small nerve fibers in the skin is so common among chronic neuropathies, namely small fiber neuropathy.
They examined human dorsal root ganglia as well, finding that this transfer process is not limited to mice. Comparing tissue from donors with and without diabetes, the authors found that diabetic SGCs transferred a significantly reduced number of mitochondria to neurons. Their results thus far indicated that diabetes and some chemotherapy agents can block mitochondrial transfer, thus sapping a nerve's energy reserves and setting the table for nerve injury. They next aimed to determine if restoring mitochondria transfer would reverse the effects.
To find out, they induced either diabetic or chemotherapy-like conditions in two separate groups of mice. The researchers then collected and transferred healthy human SGCs into the diabetes model and healthy mouse SGCs into the chemotherapy model. Both sets of experiments demonstrated that the transferred SGCs increased the animals' pain threshold.
The team achieved similar results when they isolated mitochondria from SGCs first and then transferred the isolated organelles into the animal models. In addition to improved pain thresholds, the team also showed that the treatment potentially restored small nerve branches in the diabetes model.
These initial results are promising and potentially unlock a new channel by which neuropathy could be treated, however, the scientists note there is still much to learn by pulling at the thread of mitochondrial transfer. For instance, does a cell type analogous to SGCs, known as astrocytes, engage in a similar process to power neurons in the brain and spinal cord?
"There's only one way to find out," Ji said. "This and other questions will guide what we examine next."
