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George DS, Hackelberg S, Jayaraj ND, et al. Mitochondrial calcium uniporter deletion prevents painful diabetic neuropathy by restoring mitochondrial morphology and dynamics. Pain. 2021;doi: 10.1097/j.pain.0000000000002391.
George, D. S., Hackelberg, S., Jayaraj, N. D., Ren, D., Edassery, S. L., Rathwell, C., Miller, R. E., Malfait, A. M., Savas, J. N., Miller, R. J., & Menichella, D. M. (2021). Mitochondrial calcium uniporter deletion prevents painful diabetic neuropathy by restoring mitochondrial morphology and dynamics. Pain, . https://doi.org/10.1097/j.pain.0000000000002391
George, Dale S, et al. "Mitochondrial calcium uniporter deletion prevents painful diabetic neuropathy by restoring mitochondrial morphology and dynamics." Pain vol. (2021). doi: https://doi.org/10.1097/j.pain.0000000000002391
George DS, Hackelberg S, Jayaraj ND, Ren D, Edassery SL, Rathwell C, Miller RE, Malfait AM, Savas JN, Miller RJ, Menichella DM. Mitochondrial calcium uniporter deletion prevents painful diabetic neuropathy by restoring mitochondrial morphology and dynamics. Pain. 2021 Jul 02; doi: 10.1097/j.pain.0000000000002391. Epub 2021 Jul 02. PMID: 34232927; PMCID: PMC8720329.
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Pain. 2021 Jul 02; doi: 10.1097/j.pain.0000000000002391. Epub 2021 Jul 02.

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

Pain

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

Affiliations

  1. Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, Department of Internal Medicine, Rush Medical College, Chicago, IL, USA.

PMID: 34232927 PMCID: PMC8720329 DOI: 10.1097/j.pain.0000000000002391

Abstract

ABSTRACT: 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. 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 two 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 (MCU) 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 MCU, 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.

Copyright © 2021 International Association for the Study of Pain.

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