Mitochondrial calcium uniporter deletion prevents painful diabetic neuropathy by restoring mitochondrial morphology and dynamics

Dale S. George, Sandra Hackelberg, Nirupa D. Jayaraj, Dongjun Ren, Seby L. Edassery, Craig A. Rathwell, Rachel E. Miller, Anne Marie Malfait, Jeffrey N. Savas, Richard J. Miller, Daniela M. Menichella*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Painful diabetic neuropathy (PDN) is an intractable complication affecting 25% of diabetic patients. Painful diabetic neuropathy is characterized by neuropathic pain accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability, resulting in calcium overload, axonal degeneration, and loss of cutaneous innervation. The molecular pathways underlying these effects are unknown. Using high-throughput and deep-proteome profiling, we found that mitochondrial fission proteins were elevated in DRG neurons from mice with PDN induced by a high-fat diet (HFD). In vivo calcium imaging revealed increased calcium signaling in DRG nociceptors from mice with PDN. Furthermore, using electron microscopy, we showed that mitochondria in DRG nociceptors had fragmented morphology as early as 2 weeks after starting HFD, preceding the onset of mechanical allodynia and small-fiber degeneration. Moreover, preventing calcium entry into the mitochondria, by selectively deleting the mitochondrial calcium uniporter from these neurons, restored normal mitochondrial morphology, prevented axonal degeneration, and reversed mechanical allodynia in the HFD mouse model of PDN. These studies suggest a molecular cascade linking neuropathic pain to axonal degeneration in PDN. In particular, nociceptor hyperexcitability and the associated increased intracellular calcium concentrations could lead to excessive calcium entry into mitochondria mediated by the mitochondrial calcium uniporter, resulting in increased calcium-dependent mitochondrial fission and ultimately contributing to small-fiber degeneration and neuropathic pain in PDN. Hence, we propose that targeting calcium entry into nociceptor mitochondria may represent a promising effective and disease-modifying therapeutic approach for this currently intractable and widespread affliction. Moreover, these results are likely to inform studies of other neurodegenerative disease involving similar underlying events.

Original languageEnglish (US)
Pages (from-to)560-578
Number of pages19
JournalPain
Volume163
Issue number3
DOIs
StatePublished - Mar 1 2022

Funding

This work was supported by NIH R01 and NIH HEAL initiative supplement R01 NS104295-01, NIH/NIAMS R01 AR077691-01 (D.M.M.) and NIH and NIH/Rush University Medical Center 1R01AR064251-01 (R.J.M., A.M.M.). Jeffery Savas laboratory is supported in part by AG061787. The authors thank Dr. Rajeshwar Awatramani for helpful discussions. The authors thank Dr. Shingo Ishihara for the technical assistance with the paw hyperalgesia experiments and Dr. Vania Apkarian's lab and Maria Virginia Centeno for allowing us to use the Ugo Basile apparatus. The authors thank Lennell Reynolds Jr at the Northwestern University Center for Advanced Microscopy for help with the electron microscope. The authors thank Dr. Jeffery Molkentin (Cincinnati Children's Hospital Medical Center) for the generous gift of the MCU mice. fl/fl

Keywords

  • Dorsal root ganglion
  • Mitochondria
  • Mitochondrial calcium uniporter
  • Neuropathic pain
  • Painful diabetic neuropathy

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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