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.
Highlights
Capsaicin (8-methyl-N-vanillyl-6-noneamide), a chili pepper irritant [71], is commonly used as a local analgesic in individuals with sensory nerve disorders such as diabetic neuropathy [7, 18]
DRG dorsal root ganglia. b Axonal pathologies in epidermal nerves after daily capsaicin injections. b1 Epidermal nerve terminals were evenly distributed in controls (b1 inset, arrowheads)
The proportion of mitochondria
Summary
Capsaicin (8-methyl-N-vanillyl-6-noneamide), a chili pepper irritant [71], is commonly used as a local analgesic in individuals with sensory nerve disorders such as diabetic neuropathy [7, 18]. By the activation of the transient receptor potential vanilloid receptor 1 (TRPV1), which is expressed on sensory axons [9, 43], capsaicin induces a nonselective cationic influx, leading to Ca2+-dependent desensitization and eventually local denervation of the skin [3, 23, 45, 47]. Previous studies have described the effects of capsaicin on neuronal cell bodies [16, 36], but less is known about the cellular and molecular alterations that cause distal axonal degeneration. Focal accumulation of mitochondria and cytoskeleton in axonal swellings suggests that energy failure and Ca2+ overload play pivotal roles in axonal degeneration [5, 42, 50]
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