Restoring cellular energy transfer heals nerve damage in mice

A new study suggests that the sensory neurons responsible for pain rely on a designated delivery service to receive their energy. Researchers have discovered that support cells surrounding these neurons physically transfer mitochondria—the power plants of the cell—through tiny, tube-like bridges. When this supply chain breaks down, it appears to contribute to the nerve damage and pain associated with chemotherapy and diabetes. The study was published in the journal Nature.

Our bodies possess an intricate network of sensory neurons that transmit information about touch, temperature, and pain to the central nervous system. These cells face a distinct logistical challenge. Their primary bodies are clustered in bundles called dorsal root ganglia located near the spine, but their thread-like extensions, called axons, must reach all the way to the toes and fingertips. Maintaining energy levels across such vast distances is energetically expensive.

Biologists have historically understood that mitochondria are generated within a cell and remain there to produce energy. However, the extreme length of sensory axons raises questions about how neurons maintain enough power to function and repair themselves. A single neuron extending from the human spine to the foot can be up to one meter long. Manufacturing and transporting mitochondria from the cell body to the distant terminals presents a formidable hurdle for the cell.

Jing Xu and Ru-Rong Ji, researchers at the Duke University Medical Center, hypothesized that these neurons might not be working alone. They focused on satellite glial cells, a type of support cell that completely envelopes the bodies of sensory neurons. For decades, scientists believed these glial cells merely provided structural cushioning and chemical balance. Xu and Ji investigated whether these cells might also serve as external batteries.

The research team, led by Xu and Ji, began their investigation by growing mouse neurons and satellite glial cells together in a laboratory setting. They utilized fluorescent dyes to label the mitochondria within the glial cells. Through time-lapse imaging, they observed the glowing mitochondria leaving the glial cells and entering the neurons. This offered visual proof that energy packets were moving between distinct cells.

To understand how this transfer occurred, the team employed high-resolution electron microscopy. This imaging technique revealed physical connections linking the outer membranes of the support cells to the neurons. These connections are known as tunneling nanotubes. They act as transient bridges that allow cellular cargo to pass from one interior environment to another.

The researchers identified the structural components of these bridges. They found that the nanotubes are constructed from actin, a protein that forms the skeleton of cells. They also identified a specific motor protein called myosin 10. This protein appears to drive the formation of the tunnels and facilitates the transport of mitochondria through them.

When the researchers genetically removed the ability of the glial cells to produce myosin 10, the transfer of mitochondria stopped. The study showed that without this external infusion of energy, the neurons struggled. Their ability to manage oxidative stress declined, and their electrical activity became unstable. This suggested that the donation of mitochondria is not just a bonus but a requirement for neuronal health.

The team then sought to determine if this mechanism operates inside living animals. They utilized a specialized strain of mice engineered to produce fluorescent mitochondria. By combining this with advanced microscopy, they documented the existence of tunneling nanotubes within the dorsal root ganglia of live mice. The images confirmed that the phenomenon observed in the petri dish was a natural biological process.

The investigation then turned to the relationship between mitochondrial transfer and neuropathy. Peripheral neuropathy is a condition involving nerve damage that causes chronic pain, tingling, and numbness. It is a frequent side effect of chemotherapy drugs like paclitaxel and a common complication of diabetes. The researchers administered paclitaxel to mice to mimic chemotherapy-induced neuropathy.

In the mice treated with chemotherapy, the number of tunneling nanotubes dropped precipitously. The transfer of mitochondria from glial cells to neurons was severely impeded. The researchers observed a similar breakdown in transport in mice bred to model type 2 diabetes. In both models, the reduction in mitochondrial delivery correlated with increased sensitivity to pain and the degeneration of nerve fibers in the skin.

To verify the relevance to human health, the team analyzed tissue samples from human donors. They compared dorsal root ganglia from healthy donors with those from donors who had a history of diabetes. The diabetic tissue displayed a marked reduction in the genetic expression of myosin 10. This finding supports the idea that the mechanism failure seen in mice also occurs in humans with neuropathy.

The most distinct evidence for the protective role of this transfer came from “rescue” experiments. The researchers isolated healthy satellite glial cells and injected them directly into the dorsal root ganglia of mice suffering from neuropathy. This procedure restored the supply of mitochondria to the struggling neurons.

The results of this intervention were measurable and positive. The mice treated with healthy glial cells exhibited a higher tolerance for pain compared to untreated controls. Furthermore, the treatment appeared to resolve the physical damage to the nerves. The density of nerve fibers in the skin, which typically dies back during neuropathy, showed signs of regeneration.

The researchers took this line of inquiry one step further by bypassing the cells entirely. They isolated pure mitochondria from healthy glial cells and injected the organelles directly into the damaged nerve clusters. This direct injection of mitochondria achieved similar results. The pain behaviors in the mice subsided, and the nerves began to recover. This suggests that the mitochondria themselves are the therapeutic agent.

There are caveats to these findings that require consideration. The study focused exclusively on the dorsal root ganglia and peripheral sensory neurons. It remains unknown if similar transfer mechanisms occur in the brain or spinal cord, where a different type of support cell known as an astrocyte interacts with neurons. The central nervous system has a different architecture, so the processes may not be identical.

Additionally, the precise signals that trigger the formation of these nanotubes remain to be identified. The researchers know that the glial cells initiate the connection, but they do not yet know what chemical distress signal the neuron sends to request aid. Understanding this signaling pathway would be necessary to develop drugs that could stimulate the process without invasive injections.

The feasibility of translating this into a human therapy also presents challenges. Injecting cells or mitochondria directly into nerve bundles is an invasive procedure. Future research would need to determine if systemic treatments could stimulate the body’s existing glial cells to repair their connections and resume mitochondrial transfer.

This study fundamentally alters the understanding of how neurons sustain themselves. It portrays the sensory neuron not as an independent entity but as a cell that is metabolically coupled to its neighbors. The satellite glial cells act as a life-support system, constantly replenishing the energy reserves of the neuron. When that support line is cut, the neuron becomes vulnerable to disease and injury.

The findings offer a new target for treating peripheral neuropathy. Current treatments often focus on dampening the electrical signals of pain. This research suggests a restorative approach. By repairing the energy supply chain, it may be possible to heal the damaged nerves rather than simply masking the symptoms. The work opens a new avenue for investigating how cellular cooperation maintains the health of the nervous system.

The study, “Mitochondrial transfer from glia to neurons protects against peripheral neuropathy,” was authored by Jing Xu, Yize Li, Charles Novak, Min Lee, Zihan Yan, Sangsu Bang, Aidan McGinnis, Sharat Chandra, Vivian Zhang, Wei He, Terry Lechler, Maria Pia Rodriguez Salazar, Cagla Eroglu, Matthew L. Becker, Dmitry Velmeshev, Richard E. Cheney & Ru-Rong Ji.