Mitochondria Transfer From Satellite Glial Cells May Drive Chronic Nerve Pain

Researchers have found that neurons responsible for sensing pain stay alive by taking mitochondria directly from neighbouring support cells.

When this exchange is interrupted, neurons begin to fire incorrectly and deteriorate, revealing a previously unknown process that may underlie chronic nerve pain.

Energy gifts in nerves

Within the dorsal root ganglia - groups of nerve cells positioned close to the spinal cord - support cells encase pain-sensing neurons and provide them with additional energy.

Scientists at Duke University mapped this energy transfer in detail using mouse cells, living mice and donated human tissue.

Dr Ru-Rong Ji found that mitochondria, the structures within cells that convert oxygen into usable energy, pass from nearby cells into neurons.

As certain nerve fibres extend for more than 0.9 metres, receiving a new local supply could avert energy shortages far away from the cell body.

Tubes that appear and vanish

Satellite glial cells, which support and surround every sensory neuron, formed slender cellular connections straight to the neuron’s surface.

These links were made from tunnelling nanotubes - short-lived tubes between cells that form and disappear rapidly - and transported mitochondria directly into neurons.

A protein known as MYO10, which helps create cellular extensions, drove the nanotubes outwards until they reached the neurons.

Since the tubes broke down in only tens of minutes, the cells needed to construct them repeatedly, making this delivery system readily disrupted.

When shipping gets blocked

Preventing the mitochondrial transfer in healthy mice rapidly increased their sensitivity to pain, while injured nerve fibres began to display evidence of deterioration.

Deprived of sufficient available energy, sensory neurons became less able to regulate their electrical activity, making abnormal firing easier to provoke.

This pattern resembled peripheral neuropathy - damage to nerves outside the brain and spinal cord - which may produce stabbing pain.

Replacing the missing energy source, instead of merely dulling pain signals, could potentially shield nerves against long-term damage.

Diseases that disrupt supply

For people with diabetes, pain and numbness in the nerves can develop gradually, often affecting the feet first. Following chemotherapy, toxic stress may harm sensory fibres, causing tingling and weakness that can continue after treatment has ended.

Laboratory studies in mice with both conditions found that fewer mitochondria travelled from satellite glial cells to neurons.

As this transfer declines, minor damage may accumulate within long nerves, creating the conditions for persistent pain that is difficult to treat.

Why small fibres suffer

Within nerve bundles, larger fibres received a greater quantity of mitochondria, whereas very small fibres were given less support.

However, why larger fibres gain more mitochondrial support is still uncertain. The researchers observed this unexplained preference throughout the nerve fibres they studied, leaving unresolved why smaller fibres remain more exposed.

For patients, this disparity may help account for small fibre neuropathy - injury to thin pain fibres - which occurs in diabetes and after chemotherapy.

Human clues in tissue

As well as in mice, donated human nerve tissue revealed the same close enclosure of sensory neurons by satellite glial cells.

In the human specimens, MYO10 activity was high in satellite glial cells but was reduced in tissue from donors with diabetes.

Reduced MYO10 produced fewer stable nanotubes, meaning that cultured human neurons absorbed fewer mitochondria when matched with diabetic cells.

Consequently, one protein now appears to be among the processes that disease can interrupt at an early stage, well before nerves begin to fail.

Borrowed power as therapy

In mice with nerve injuries, supplying healthy satellite glial cells or purified mitochondria to the dorsal root ganglia reduced nerve pain for up to 2 days.

By reinstating energy production within neurons, transferred mitochondria lowered cellular stress and helped prevent damaged nerves from firing continuously.

When researchers inhibited MYO10 in the donor glia, the protective benefit was lost, indicating that the transfer itself was more important than simply having the cells present.

Future treatments would require a safe method of getting mitochondria to the appropriate nerve hubs without triggering inflammation.

Risks before real use

At present, this research is limited to mice and donated tissue, so it remains unknown whether mitochondrial transfer can safely be increased in people.

Mitochondria delivered by injection could also cause inflammation, which might intensify pain rather than relieve it.

Accessing the dorsal root ganglia in patients would additionally demand highly accurate injections near the spine, a procedure that brings genuine risks.

Long-term research must establish durability and dosing, as well as whether small fibres, rather than only medium and large ones, can be protected.

Future research directions

For decades, textbooks generally portrayed glial cells as basic support cells, yet this work showed that they physically pass cargo to neurons.

Through direct nanotube contact, support cells could provide assistance precisely where an under-pressure nerve requires it most.

“If they can transport mitochondria, such a very large organelle, in that tube, then you can transport many other things, right?” Ji suggested.

Researchers can now investigate whether these same connections also carry signals that reduce pain or signals that sustain nerve inflammation.

The study recast nerve pain as a supply issue, in which energy assistance from neighbouring cells preserves stable signalling and intact nerves.

Demonstrating the same transfer in living patients will require careful clinical trials and improved methods for targeting the most severely affected small fibres.