Mitochondrial Calcium Uniporter Deletion Prevents Painful Diabetic Neuropathy by Restoring Mitochondrial Morphology and Dynamics

George, Dale; Hackelberg, Sandra; Jayaraj, Nirupa D.; Ren, Dongjun; Edaserry, Seby; Rathwell, Craig A.; Miller, Rachel K.; Savas, Jeffery; Miller, Richard H.; Menichella, Daniela

doi:10.1016/j.jpain.2021.03.015

“…An essential factor in the trafficking of mitochondria is active Drp1 [ 35 ]. Dale et al discovered increased DRG neuronal expressions of mitochondrial fission proteins in mice with a high-fat diet- (HFD-) triggered painful diabetic neuropathy (PDN) [ 36 ]. These results are consistent with our findings.…”

Section: Discussionmentioning

confidence: 99%

Perisciatic Nerve Dexmedetomidine Alleviates Spinal Oxidative Stress and Improves Peripheral Mitochondrial Dynamic Equilibrium in a Neuropathic Pain Mouse Model in an AMPK-Dependent Manner

Mu

¹

,

Mei

²

,

Chen

³

et al. 2022

View full text Add to dashboard Cite

Neuropathic pain (NPP) is a debilitating clinical condition that presently has few effective treatments. NPP is caused by uncontrolled central oxidative stress and inflammation. Preliminary studies indicate that dexmedetomidine (DEX), an agonist of the alpha-2 adrenergic receptor, is beneficial for treating NPP. In this paper, the effects of administering DEX around injured nerves in a chronic constriction injury- (CCI-) induced neuropathic pain mouse model are investigated. According to the results, the perineural DEX significantly reversed the decline in the mechanical threshold and thermal latency in CCI mice ( p < 0.001 ). In the peripherally affected ischiadic nerve, the perineuronal DEX upregulated the expressions of pAMPK, OPA1, and SNPH but not Drp1 or KIF5B. The aforementioned effects of administering DEX can be partially reversed by compound C, a selective and reversible inhibitor of AMP-activated protein kinase (AMPK). Furthermore, it was found that perineural DEX significantly inhibited the CCI-induced upregulation of the immediate early gene c-Fos, overexpression of the inflammatory factors tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), attenuation of the NADH dehydrogenase complexes I, II, III, and IV, and the repression of ATP, SOD, and GSH in the dorsal horn of the spinal cord (DHSC) ( p < 0.01 ). These findings indicate that perineuronal DEX protected the injured ischiadic nerves and attenuated neuropathic pain via AMPK activation to improve energy supply in the peripheral injured nerves, alleviate the inflammatory factor release, and inhibit oxidative stress in the DHSC.

show abstract

“…Additionally, metabolites can be influenced directly by endogenous and exogenous factors and are direct players in biochemical processes, thus offering a strong descriptor of molecular phenotype. A few studies have identified metabolomic and proteomic trends suggestive of disrupted energy metabolism and mitochondrial function in DRG of diabetic rodents [20][21][22][23]. Better understanding of molecular regulation with painful conditions in human systems is vital for development of novel therapeutics [24].…”

Section: Introductionmentioning

confidence: 99%

Integrative Multiomic Analyses of Diabetic Neuropathic Pain in Dorsal Root Ganglia: Proteomics, Phospho-proteomics, and Metabolomics

Doty

¹

,

Yun²,

Wang

³

et al. 2022

Preprint

0

View full text Add to dashboard Cite

Diabetic peripheral neuropathy (DPN) is characterized by spontaneous pain in the extremities. Incidence of DPN continues to rise with the global diabetes epidemic. However, there remains a lack of safe, effective analgesics to control this chronic painful condition. Dorsal root ganglia (DRG) contain soma of sensory neurons and modulate sensory signal transduction into the central nervous system. In this study, we aimed to gain a deeper understanding of changes in molecular pathways in the DRG of DPN patients with chronic pain. We recently reported transcriptomic changes in the DRG with DPN. Here, we expand upon those results with integrated metabolomic, proteomic, and phospho-proteomic analyses to compare the molecular profiles of DRG from DPN donors and DRG from control donors without diabetes or chronic pain. Our analyses identified decreases of select amino acids and phospholipid metabolites in the DRG from DPN donors, which are important for cellular maintenance. Additionally, our analyses revealed changes suggestive of extracellular matrix (ECM) remodeling and altered mRNA processing. These results reveal new insights into changes in the molecular profiles associated with DPN.

show abstract

“…A few studies have identi ed metabolomic and proteomic trends suggestive of disrupted energy metabolism and mitochondrial function in DRG of diabetic rodents [20][21][22][23]. Better understanding of molecular regulation with painful conditions in human systems is vital for development of novel therapeutics [24].…”

Section: Introductionmentioning

confidence: 99%

Integrative Multiomic Analyses of Diabetic Neuropathic Pain in Dorsal Root Ganglia: Proteomics, Phospho-proteomics, and Metabolomics

Doty

¹

,

Yun

²

,

Wang

³

et al. 2022

Preprint

0

View full text Add to dashboard Cite

Diabetic peripheral neuropathy (DPN) is characterized by spontaneous pain in the extremities. Incidence of DPN continues to rise with the global diabetes epidemic. However, there remains a lack of safe, effective analgesics to control this chronic painful condition. Dorsal root ganglia (DRG) contain soma of sensory neurons and modulate sensory signal transduction into the central nervous system. In this study, we aimed to gain a deeper understanding of changes in molecular pathways in the DRG of DPN patients with chronic pain. We recently reported transcriptomic changes in the DRG with DPN. Here, we expand upon those results with integrated metabolomic, proteomic, and phospho-proteomic analyses to compare the molecular profiles of DRG from DPN donors and DRG from control donors without diabetes or chronic pain. Our analyses identified decreases of select amino acids and phospholipid metabolites in the DRG from DPN donors, which are important for cellular maintenance. Additionally, our analyses revealed changes suggestive of extracellular matrix (ECM) remodeling and altered mRNA processing. These results reveal new insights into changes in the molecular profiles associated with DPN.

show abstract

Mitochondrial Calcium Uniporter Deletion Prevents Painful Diabetic Neuropathy by Restoring Mitochondrial Morphology and Dynamics

Cited by 4 publications

References 0 publications

Perisciatic Nerve Dexmedetomidine Alleviates Spinal Oxidative Stress and Improves Peripheral Mitochondrial Dynamic Equilibrium in a Neuropathic Pain Mouse Model in an AMPK-Dependent Manner

Perisciatic Nerve Dexmedetomidine Alleviates Spinal Oxidative Stress and Improves Peripheral Mitochondrial Dynamic Equilibrium in a Neuropathic Pain Mouse Model in an AMPK-Dependent Manner

Integrative Multiomic Analyses of Diabetic Neuropathic Pain in Dorsal Root Ganglia: Proteomics, Phospho-proteomics, and Metabolomics

Integrative Multiomic Analyses of Diabetic Neuropathic Pain in Dorsal Root Ganglia: Proteomics, Phospho-proteomics, and Metabolomics

Contact Info

Product

Resources

About