Energy Gifts in Nerves: New Understanding of Chronic Pain
Researchers at Duke University have uncovered a surprising mechanism behind chronic nerve pain: pain-sensing nerve cells rely on direct imports of mitochondria – the cell’s power plants – from neighboring support cells. Disrupting this transfer leads to neuronal misfiring and deterioration, offering a new target for pain therapies.
The research, detailed in the journal Nature, focused on the dorsal root ganglia, clusters of nerve cells located near the spinal cord. These ganglia are critical for relaying sensory information, including pain signals, to the brain.
How Mitochondria Move to Sensory Neurons
The study revealed that specialized support cells, called satellite glial cells, actively supply mitochondria to the pain-sensing neurons. These mitochondria aren’t created within the neurons themselves, but are instead delivered via thin cellular bridges formed by structures called tunneling nanotubes. These nanotubes are temporary, constantly appearing and vanishing, requiring frequent rebuilding.
A protein called MYO10 plays a crucial role in this process. MYO10 assists in building the cellular extensions that form the nanotubes, enabling them to reach the neurons and deliver the vital mitochondria. The researchers found that the efficiency of this transfer is surprisingly high, despite the transient nature of the nanotubes.
Blocking Mitochondrial Transfer Induces Pain
To demonstrate the importance of this mitochondrial handoff, the Duke team blocked the transfer in healthy mice. The results were striking: pain sensitivity increased rapidly, and nerve fibers began to show signs of damage. Without a sufficient energy supply, the sensory neurons lost control of their electrical signaling, leading to abnormal firing patterns.
This pattern closely mirrored the symptoms of peripheral neuropathy, a condition characterized by nerve damage outside the brain and spinal cord, often manifesting as stabbing pain. The findings suggest that restoring mitochondrial supply, rather than simply blocking pain signals, could offer a more effective long-term solution for nerve pain.
Implications for Diabetes and Chemotherapy-Induced Pain
The research also sheds light on the origins of chronic pain associated with conditions like diabetes and chemotherapy. In mice modeling these conditions, the researchers observed a significant reduction in the number of mitochondria being transferred from satellite glial cells to neurons.
In diabetes, nerve pain and numbness often develop gradually, particularly in the feet. Chemotherapy can also cause nerve damage, leading to tingling and weakness that persists even after treatment ends. The reduced mitochondrial transfer in these scenarios suggests that a buildup of small injuries within the long nerve fibers contributes to the development of stubborn, difficult-to-treat pain.
Small Fiber Vulnerability and Human Tissue Evidence
Interestingly, the study found that smaller nerve fibers received less mitochondrial support than larger fibers, even though the underlying mechanism appeared consistent across fiber types. The reason for this disparity remains unclear, but it could explain why small fiber neuropathy – damage to thin pain fibers – is commonly observed in diabetes and chemotherapy patients.
Further supporting the findings, analysis of donated human nerve tissue revealed the same close interaction between satellite glial cells and sensory neurons. In samples from individuals with diabetes, MYO10 activity was lower, resulting in fewer stable nanotubes and reduced mitochondrial uptake by neurons.
Potential Therapeutic Approaches
The researchers explored potential therapeutic interventions in injured mice. Delivering healthy satellite glial cells or purified mitochondria to the dorsal root ganglia temporarily alleviated nerve pain for up to two days. This suggests that restoring energy production within neurons can reduce cell stress and prevent damaged nerves from firing uncontrollably.
However, blocking MYO10 in the donor glial cells eliminated the protective effect, emphasizing the importance of the transfer process itself, rather than simply the presence of the cells.
Challenges and Future Research
While promising, the research is still in its early stages. The current findings are based on studies in mice and donated human tissue, and it remains unknown whether boosting mitochondrial transfer can be safely and effectively achieved in humans.
Potential risks include inflammation triggered by injected mitochondria, which could worsen pain. Reaching the dorsal root ganglia in patients would also require precise injections near the spine, a procedure with inherent risks.
Future research will focus on developing safe and targeted methods for delivering mitochondria to the affected nerve hubs. Researchers also plan to investigate whether the same connections used for mitochondrial transfer can be utilized to deliver other therapeutic molecules, such as signals that calm pain or reduce inflammation. The study published reframes chronic nerve pain not simply as a signaling problem, but as a fundamental energy supply issue.
