Mitochondrial fission augments capsaicin-induced axonal degeneration

Abstract

Capsaicin, an agonist of transient receptor potential vanilloid receptor 1, induces axonal degeneration of peripheral sensory nerves and is commonly used to treat painful sensory neuropathies. In this study, we investigated the role of mitochondrial dynamics in capsaicin-induced axonal degeneration. In capsaicin-treated rodent sensory axons, axonal swellings, decreased mitochondrial stationary site length and reduced mitochondrial transport preceded axonal degeneration. Increased axoplasmic Ca2+ mediated the alterations in mitochondrial length and transport. While sustaining mitochondrial transport did not reduce axonal swellings in capsaicin-treated axons, preventing mitochondrial fission by overexpression of mutant dynamin-related protein 1 increased mitochondrial length, retained mitochondrial membrane potentials and reduced axonal loss upon capsaicin treatment. These results establish that mitochondrial stationary site size significantly affects axonal integrity and suggest that inhibition of Ca2+-dependent mitochondrial fission facilitates mitochondrial function and axonal survival following activation of axonal cationic channels.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1354-3) contains supplementary material, which is available to authorized users.

Ca2+ and calpain mediate capsaicin-induced ablation of axonal terminals expressing transient receptor potential vanilloid 1

“…Our results from FCCP/oligomycin suggested that Ca 2ϩ release from mitochondria alone or depolarization of mitochondrial membrane potential was not sufficient to induce ablation of TRPV1-lineage terminals. These results do not exclude a contribution of mitochondria, however, and our data do not necessarily contradict a recent report suggesting a role for mitochondria in capsaicin-induced degeneration of axons (21). Capsaicin increases mitochondrial fission, which, in turn, decreases mitochondrial stationary site sizes in a Ca 2ϩ -dependent manner.…”

“…On the other hand, it was also suggested that capsaicin depolarizes mitochondrial membrane potential by direct action on mitochondria in sensory neurons (34), which potentially contributes to cytotoxicity. Furthermore, it was recently suggested that Ca 2ϩ -dependent mitochondrial fission augments capsaicin-induced axonal degeneration (21). However, it is still unclear whether mitochondria play a dominant role in capsaicin-induced ablation of nociceptive afferent terminals and how mitochondria contribute to capsaicin-induced axonal ablation.…”

“…Although apoptosis of neurons and selective degeneration of axons share common mechanisms, distinct pathways mediate the two processes (20). Recently, capsaicin-induced axonal degeneration was shown to be associated with Ca 2ϩ -dependent fission of axonal mitochondria (21), which suggests a common mitochondrion-dependent mechanism. In our view, however, the mechanisms underlying capsaicin-induced axonal ablation are distinct from and should be determined independent of capsaicin-induced neuronal death.…”

Use of Capsaicin to Treat Pain: Mechanistic and Therapeutic Considerations

“…Studies of mitochondrial fission support the role of mitochondria [146]. In dissociated DRG neurons, capsaicin induced axonal swelling, which was accompanied by reduction in the length of the mitochondria and motility within axons.…”

Altered Mitochondrial Anatomy of Trigeminal Ganglia Neurons in Diabetes

“…In neurons, hyperglycemia increases Mf and subsequently creates small and damaged mitochondria at this levels, whilst a reduction of Mf increases cellular survival (Edwards et al, ). It was established that inhibition of Ca 2+ ‐dependent Mf facilitates mitochondrial function and axonal surviving in capsaicin‐induced degeneration of rodent sensory axons (Chiang et al, ).…”