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Painful diabetic neuropathy (PDN) is an intractable complication affecting 25% of
diabetic patients. PDN is characterized by neuropathic pain accompanied by dorsal
root ganglion (DRG) nociceptor hyperexcitability, resulting in calcium overload, axonal
degeneration, and loss of cutaneous innervation. However, the underlying molecular
pathways responsible for these effects are unknown. Using highly stringent quantitative
proteomic analyses, we found that mitochondrial proteins are differentially expressed
in DRG neurons from mice with PDN caused by a high fat diet (HFD). In particular,
mitochondrial fission proteins were overexpressed. Electron microscopy demonstrated
fragmented mitochondrial morphology in DRG nociceptors. In vivo calcium imaging revealed
increased calcium signaling in Nav1.8-expressing DRG neurons of HFD mice. Selectively
deleting the mitochondrial calcium uniporter from these neurons restored normal mitochondrial
morphology and dynamics, prevented axonal degeneration, and reversed mechanical allodynia.
Hence, we propose that targeting calcium entry into nociceptor mitochondria may be
a promising therapeutic approach for PDN patients. Moreover, these results may illuminate
other neurodegenerative diseases involving similar underlying events 5R01NS104295-02
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© 2021 Published by Elsevier Inc.
