New research, supported by the National Institutes of Health (NIH) and published in the journal Nature, has identified a mechanism involving the transfer of mitochondria between satellite glial cells (SGCs) and sensory neurons. This energy-transfer process, found to be disrupted in conditions leading to nerve damage (neuropathy) such as those caused by chemotherapy and diabetes, was observed to reduce pain and promote nerve regeneration when restored in animal models. The findings suggest a potential area for the development of new neuropathy treatments.
Energy Transfer Mechanism in Sensory Neurons
Sensory neurons, which transmit signals over significant distances from the spinal column to the extremities, have high energy requirements. The study found that satellite glial cells (SGCs), support cells that encase sensory neurons within dorsal root ganglia (clusters of nerve cells near the spine), contribute to this energy supply by transferring mitochondria to neurons. Mitochondria are the organelles responsible for producing energy within cells.
This transfer occurs primarily through microscopic structures called tunneling nanotubes (TNTs), which form between SGCs and neurons. Observations using high-resolution imaging in cultured mouse SGCs and neurons, whole dorsal root ganglia from mice, and human dorsal root ganglia confirmed the formation of these tubes and the movement of mitochondria through them. SGCs were identified as the primary initiators of TNT formation, indicating a predominant unidirectional transfer of mitochondria from SGCs to neurons. The MYO10 protein was found to be crucial for the formation and extension of these nanotubes. Additional transfer methods, such as within small vesicles or through direct membrane channels, were also noted.
Disruption in Neuropathy and Consequences
The research team observed that this mitochondrial transfer process is impaired in animal models of chemotherapy-induced and diabetic neuropathy. Analysis of human dorsal root ganglia also indicated that SGCs from diabetic donors transferred fewer mitochondria to neurons compared to non-diabetic controls.
When mitochondrial transfer was disrupted, nerve fibers exhibited degeneration, which can lead to pain, tingling, and numbness, particularly in extremities. In mice, disruptions led to increased pain sensitivity, nerve damage, and abnormal nerve firing. Smaller neurons were found to be particularly vulnerable to energy depletion, experiencing an earlier loss of mitochondria and appearing to receive fewer mitochondria from SGCs compared to larger neurons. This differential transfer may contribute to the prevalence of small fiber neuropathy.
Therapeutic Potential
Researchers investigated whether restoring mitochondrial transfer could mitigate these effects. In experiments where diabetic or chemotherapy-like conditions were induced in mice, the introduction of healthy human SGCs (into the diabetes model) or healthy mouse SGCs (into the chemotherapy model) resulted in an increased pain threshold. Similar outcomes were achieved by isolating mitochondria from healthy SGCs and directly transferring them into the animal models. This intervention was associated with a 40-50% reduction in pain behaviors in mice within 24 hours, with pain relief lasting several days in some instances. The treatment was also linked to a potential restoration of small nerve branches in the diabetes model. It was noted that mitochondria sourced from individuals with diabetes did not demonstrate a therapeutic effect.
Future Research Directions
These initial findings suggest a potential new area for the development of neuropathy treatments that target cellular energy supply. Further investigation is required to fully understand the mechanisms of mitochondrial shuttling between glial cells and neurons in both healthy and diseased states, including the use of high-resolution imaging. Researchers also plan to explore whether analogous cell types, such as astrocytes, engage in similar energy transfer processes to neurons in the brain and spinal cord.
The study contributes to an evolving understanding of cell biology, where cells can share energy under stress conditions, and highlights a more extensive connection between neurons and glial cells than previously understood. This research may have broader implications for other medical conditions involving cellular energy deficits.
Study Details
The study was led by Ru-Rong Ji, Ph.D., a professor at Duke University School of Medicine and director of the Center for Translational Pain Medicine. It was published in Nature and received support from the National Institutes of Health, including the National Institute of Neurological Disorders and Stroke (NINDS), the Department of Defense, and the Duke Department of Anesthesiology, among other organizations.