Mitochondrial transfer from glia to neurons protects against peripheral neuropathy.

Abstract

Primary sensory neurons in dorsal root ganglia (DRG) have long axons and a high demand for mitochondria, and mitochondrial dysfunction has been implicated in peripheral neuropathy after diabetes and chemotherapy^1,2. However, the mechanisms by which primary sensory neurons maintain their mitochondrial supply remain unclear. Satellite glial cells (SGCs) in DRG encircle sensory neurons and regulate neuronal activity and pain³. Here we show that SGCs are capable of transferring mitochondria to DRG sensory neurons in vitro, ex vivo and in vivo by the formation of tunnelling nanotubes with SGC-derived myosin 10 (MYO10). Scanning and transmission electron microscopy revealed tunnelling nanotube-like ultrastructures between SGCs and sensory neurons in mouse and human DRG. Blockade of mitochondrial transfer in naive mice leads to nerve degeneration and neuropathic pain. Single-nucleus RNA sequencing and in situ hybridization revealed that MYO10 is highly expressed in human SGCs. Furthermore, SGCs from DRG of people with diabetes exhibit reduced MYO10 expression and mitochondrial transfer to neurons. Adoptive transfer of human SGCs into the mouse DRG provides MYO10-dependent protection against peripheral neuropathy. This study uncovers a previously unrecognized role of peripheral glia and provides insights into small fibre neuropathy in diabetes, offering new therapeutic strategies for the management of neuropathic pain.