LRP1-regulated mitochondrial homeostasis in Schwann cells modulates C-fiber neuroenergetics and neuropathic pain

Alterations to Schwann cell (SC) mitochondria and the consequences to peripheral axons are poorly understood. We previously showed that the low-density lipoprotein receptor (LRP1) is upregulated in SCs after injury and contributes to the SC Repair Program. In addition, LRP1 binds and recruit phospholipid kinases to cellular membranes and regulates lipid metabolism. Using a SC-specific conditional LRP1 knock out mice (scLRP1-/-) that manifest pain related behaviors in uninjured mice, we applied a discovery-based proteomics approach to sciatic nerves. LC-MS/MS revealed significant differences in metabolic and bioenergetic pathways between scLRP1-/- nerves and littermate controls (scLRP1+/+). Specifically, proteins in the mitochondrial ATP synthase complex and in oxidative phosphorylation were upregulated in the scLRP1-/- mice. Ultrastructural analyses of sciatic nerves demonstrated that loss of LRP1 increased myelin splitting that was associated with enhanced mitochondrial density in myelinated SCs. Additionally, mitochondria displayed significant signs of damage, including reduced cristae surface area, in nonmyelinated SCs and small diameter axons in Remak bundles. Primary cultures of adult mouse SCs isolated from scLRP1-/- mice showed decreased mitochondrial membrane potentials (MMP) and mitochondrial heterogeneities, indicative of mitochondrial dysfunction. The LRP1 mediated regulation of SC mitochondria homeostasis also affected the neuroenergetics of primary sensory DRG neurons. Analysis of the DRG neuron transcriptome taken from scLRP1-/- mice showed robust alterations in the ATP biosynthetic process and oxidative phosphorylation when compared to scLRP1+/+ mice. Collectively, our study highlights the potential regulation by LRP1 in the complexity of SC bioenergetics and the importance of SC homeostasis in C-fiber function and pain.