Increasing evidence shows that metabolic changes in the neurons can contribute greatly to the development and maintenance of chronic pain. This evidence is both clear in patients experiencing chronic pain, but also on a preclinical basis. Preclinically we have observed metabolic changes in the neurons upon a transient pain stimulus. Though the pain did not persist, the metabolic changes persisted. When confronted with another, similar stimulus, this stimulus did induce chronic pain due to the metabolic and mitochondrial changes. Moreover, we have also observed evidence of mitochondrial transfer from macrophages to neurons, improving the metabolic state of the neurons and thereby ameliorating mitochondrial functioning in these cells. Most importantly, chronic pain could also be improved. We are currently further investigating these changes, when and how they occur and if we can taret these changes to prevent or reverse them.
Mitochondrial protein ATPScKMT in pain regulation
One of our ongoing projects focuses on the role of ATPScKMT (formerly known as FAM173b), a protein residing in the mitochondria. This protein was first discovered in a genome wide association study on patients with chronic pain, where it was found to be slightly altered compared to people without chronic pain. Further investigation revealed that this protein could significantly affect the development of chronic pain. Though one of the targets of this protein is now known, we are currently investigating other targets of ATPScKMT, which could explain how it affects the development and resolution of chronic pain.
Erik Duarte Lopes and Emma Tondeur are working on this project.
Our other project focuses on hIAPP-induced toxicity in Diabetic Peripheral Neuropathy (DPN)
DPN is a major complication of Type 2 diabetes, yet glucose control often fails to resolve the associated chronic pain. In these patients, increased production of human Islet Amyloid Polypeptide (hIAPP) promotes protein misfolding and the formation of toxic aggregates. We have identified that these aggregates do not just damage the pancreas, but also target the nervous system, driving neuropathic pain.
Our research focuses on the mechanisms by which hIAPP induces nerve damage. Specifically, we investigate how hIAPP oligomers interact with mitochondria in sensory neurons, leading to impaired energy metabolism and increased oxidative stress. Furthermore, we examine the role of immune cells, particularly macrophages, to determine whether defective clearance of hIAPP aggregates or activation of inflammatory pathways contributes to sustained pain hypersensitivity.
This project is led by Chilam Chan