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

Autor:	George DS; Departments of Neurology and., Hackelberg S; Departments of Neurology and., Jayaraj ND; Departments of Neurology and., Ren D; Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States., Edassery SL; Departments of Neurology and., Rathwell CA; Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States., Miller RE; Department of Internal Medicine, Rush Medical College, Chicago, IL, United States., Malfait AM; Department of Internal Medicine, Rush Medical College, Chicago, IL, United States., Savas JN; Departments of Neurology and., Miller RJ; Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States., Menichella DM; Departments of Neurology and.
Jazyk:	angličtina
Zdroj:	Pain [Pain] 2022 Mar 01; Vol. 163 (3), pp. 560-578.
DOI:	10.1097/j.pain.0000000000002391
Abstrakt:	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. (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)
Databáze:	MEDLINE
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