Mitochondrial fission augments capsaicin-induced axonal degeneration

• Published in: Acta neuropathologica 2015-01, Vol.129 (1), p.81-96
• Main Authors: Chiang, Hao, Ohno, Nobuhiko, Hsieh, Yu-Lin, Mahad, Don J., Kikuchi, Shin, Komuro, Hitoshi, Hsieh, Sung-Tsang, Trapp, Bruce D.
• Format: Article
• Language: English
• Subjects: Animals; Axons - drug effects; Axons - pathology; Axons - physiology; Calcium - metabolism; Capsaicin; Capsaicin - toxicity; Cells, Cultured; Diabetic neuropathy; Ganglia, Spinal - drug effects; Ganglia, Spinal - pathology; Ganglia, Spinal - physiology; Laboratory animals; Male; Medicine; Medicine & Public Health; Membrane Potential, Mitochondrial - drug effects; Membrane Potential, Mitochondrial - physiology; Mice, Inbred ICR; Mitochondria; Mitochondria - drug effects; Mitochondria - pathology; Mitochondria - physiology; Mitochondrial DNA; Mitochondrial Dynamics - drug effects; Mitochondrial Dynamics - physiology; Motility; Nerve Degeneration - chemically induced; Nerve Degeneration - pathology; Nerve Degeneration - physiopathology; Neurosciences; Original Paper; Pathology; Phenols (Class of compounds); Physiological aspects; Proteins; Rats, Sprague-Dawley; TRPV Cation Channels - metabolism; University colleges
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-014-1354-3

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 Ca 2+ 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 Ca 2+ -dependent mitochondrial fission facilitates mitochondrial function and axonal survival following activation of axonal cationic channels.