Journal
ACS CHEMICAL NEUROSCIENCE
Volume 12, Issue 16, Pages 3049-3059Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.1c00340
Keywords
C-terminal Hsp90 modulator; diabetic peripheral neuropathy; molecular chaperones; neuroprotection; novologues; sensory neuron
Funding
- National Institute of Diabetes, Digestive and Kidney Diseases [DK095911]
- National Institute of Neurologic Diseases [NS114355, NS075311]
- National Cancer Institute [CA120458]
Ask authors/readers for more resources
Diabetic peripheral neuropathy (DPN) is linked to altered mitochondrial bioenergetics (mtBE), and KU-596 is a small molecule neurotherapeutic that can reverse DPN symptoms by improving sensory neuron mtBE and decreasing pro-oxidant protein Txnip. This study found that KU-596 therapy improved DPN, mtBE, and mitophagy in a manner dependent on Hsp70 but not Txnip. The results suggest that KU-596 may enhance mitochondrial tolerance to diabetic stress through a mechanism involving Hsp70 and Txnip.
Diabetic peripheral neuropathy (DPN) is a complication of diabetes whose pathophysiology is linked to altered mitochondrial bioenergetics (mtBE). KU-596 is a small molecule neurotherapeutic that reverses symptoms of DPN, improves sensory neuron mtBE, and decreases the pro-oxidant protein, thioredoxin-interacting protein (Txnip) in a heat shock protein 70 (Hsp70)-dependent manner. However, the mechanism by which KU-596 improves mtBE and the role of Txnip in drug efficacy remains unknown. Mitophagy is a quality-control mechanism that selectively targets damaged mitochondria for degradation. The goal of this study was to determine if KU-596 therapy improved DPN, mtBE, and mitophagy in an Hsp70- and Txnip-dependent manner. Mito-QC (MQC) mice express a mitochondrially targeted mCherry-GFP fusion protein that enables visualizing mitophagy. Diabetic MQC, MQC X Hsp70 knockout (KO), and MQC X Txnip KO mice developed sensory and nerve conduction dysfunctions consistent with the onset of DPN. KU-596 therapy improved these measures, and this was dependent on Hsp70 but not Txnip. In MQC mice, diabetes decreased mtBE and increased mitophagy and KU-596 treatment reversed these effects. In contrast, KU-596 was unable to improve mtBE and decrease mitophagy in MQC X Hsp70 and MQC X Txnip KO mice. These data suggest that Txnip is not necessary for the development of the sensory symptoms and mitochondrial dysfunction induced by diabetes. KU-596 therapy may improve mitochondrial tolerance to diabetic stress to decrease mitophagic clearance in an Hsp70- and Txnip-dependent manner.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available