Glial Cells Transfer Mitochondria to Neurons to Prevent Peripheral Neuropathy

Peripheral sensory neurons in dorsal root ganglia (DRG) face an extraordinary bioenergetic challenge: their axons can extend over 100 cm, demanding a continuous and robust mitochondrial supply far from the cell body. Mitochondrial dysfunction has long been implicated in peripheral neuropathies arising from diabetes and chemotherapy, yet the mechanisms by which neurons maintain adequate mitochondrial reserves have remained poorly understood.

This landmark Nature study from Ji and colleagues at Duke University reveals that satellite glial cells (SGCs)—specialized glia that tightly ensheath DRG sensory neuron cell bodies—actively donate mitochondria to neurons. Using in vitro co-cultures, ex vivo whole-mount DRG tissue, and in vivo mouse models, the team demonstrated directional mitochondrial transfer from SGCs to neurons. Transfer was visualized using MitoTracker-labelled SGCs co-cultured with neurons from Trpv1:Ai9 reporter mice, with 83.3% of neurons receiving glial mitochondria. Tunnelling nanotubes (TNTs) over 30 μm in length were observed bridging SGCs and neurons, carrying mitochondria within their lumens.

Scanning and transmission electron microscopy of mouse and human DRG tissue confirmed TNT-like ultrastructures between SGCs and neurons in native tissue, containing vesicle-like bulges consistent with mitochondrial size. Mechanistically, the transfer required the unconventional motor protein MYO10, which is highly expressed in SGCs. Genetic or pharmacological blockade of TNT formation (using cytochalasin B or Y-27632) or gap junction inhibition (carbenoxolone) significantly reduced mitochondrial transfer. Inhibiting transfer in otherwise healthy mice resulted in intraepidermal nerve fibre loss, reduced mitochondrial density in DRG neurons, and development of neuropathic pain behaviours—demonstrating that basal glial-to-neuron mitochondrial transfer is physiologically essential.

Single-nucleus RNA sequencing and in situ hybridization of human DRG tissue confirmed high MYO10 expression specifically in human SGCs. Strikingly, SGCs isolated from the DRG of people with diabetes showed markedly reduced MYO10 expression and diminished capacity to transfer mitochondria to neurons. Adoptive transfer of healthy human SGCs into mouse DRG rescued nerve fibre density and pain thresholds in a MYO10-dependent manner, pointing to a translatable therapeutic strategy. The transfer was also found to be neuronal activity-dependent, as tetrodotoxin (TTX) suppressed mitochondrial transfer without affecting TNT formation rates.

This study fundamentally reframes the role of peripheral glia from passive support cells to active mitochondrial donors, and implicates impaired glial-to-neuron mitochondrial transfer as a previously unrecognized mechanism in diabetic small fibre neuropathy. The findings open new possibilities for treating peripheral neuropathy by enhancing SGC mitochondrial transfer capacity.