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Novologue Therapy Requires Heat Shock Protein 70 and Thioredoxin-Interacting Protein to Improve Mitochondrial Bioenergetics and Decrease Mitophagy in Diabetic Sensory Neurons.

ABSTRACT: 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 × Hsp70 knockout (KO), and MQC × 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 × Hsp70 and MQC × 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.

SUBMITTER: Rodriguez YA

PROVIDER: S-EPMC8456717 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Novologue Therapy Requires Heat Shock Protein 70 and Thioredoxin-Interacting Protein to Improve Mitochondrial Bioenergetics and Decrease Mitophagy in Diabetic Sensory Neurons.

Rodriguez Yssa A YA Kaur Sukmanjit S Nolte Erika E Zheng Zhang Z Blagg Brian S J BSJ Dobrowsky Rick T RT

ACS chemical neuroscience 20210803 16

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. Mitophag ...[more]

PMID: 34340312

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Project description:AimTo evaluate the potential of thioredoxin (TXN) and thioredoxin-interacting protein (TXNIP) expression as biomarkers for predicting gastric cancer recurrence.MethodsTXN and TXNIP expression levels were acquired from gene expression microarray data for 65 human gastric cancer tissues. We determined whether each gene expression level was associated with cancer recurrence and investigated the relationship between the two genes. For validation, the expression levels of TXN and TXNIP were measured by quantitative real-time reverse transcription polymerase chain reaction in 68 independent stage III gastric cancer patients. The correlation between gene expression and cancer prognosis was evaluated. Immunohistochemical staining was performed to investigate the protein expression levels of TXN and TXNIP and to characterize the expression patterns of each protein.ResultsTXN was a prognosis-related gene (P = 0.009), whereas TXNIP, a TXN inhibitor, demonstrated a negative correlation with TXN in the gene expression microarray data. In the 68 stage III patients, the expression levels of both TXN and TXNIP had a statistically significant effect on recurrence-free survival (RFS, P = 0.008 and P = 0.036, respectively). The low TXN and high TXNIP expression group exhibited a better prognosis than the other groups, and the high TXN and low TXNIP expression group exhibited a poorer prognosis (P < 0.001 for RFS and P = 0.001 for overall survival). More than half of the patients in the simultaneously high TXN and low TXNIP expression group experienced a recurrence within 1 year after curative surgery, and the 5-year survival rate of the patients in this group was 29%, compared with 89% in the low TXN and high TXNIP expression group. The TXN protein was overexpressed in 65% of the gastric cancer tissues, whereas the TXNIP protein was underexpressed in 85% of the cancer cells. In a correlation analysis, TXN and TXNIP were highly correlated with many oncogenes and tumor suppressors as well as with genes related to energy, protein synthesis and autophagy.ConclusionTXN and TXNIP are promising prognostic markers for gastric cancer, and performing personalized adjuvant treatment based on TXN and TXNIP expression levels would be an effective practice in the treatment of gastric cancer.

Dataset Information

Novologue Therapy Requires Heat Shock Protein 70 and Thioredoxin-Interacting Protein to Improve Mitochondrial Bioenergetics and Decrease Mitophagy in Diabetic Sensory Neurons.

Publications

Novologue Therapy Requires Heat Shock Protein 70 and Thioredoxin-Interacting Protein to Improve Mitochondrial Bioenergetics and Decrease Mitophagy in Diabetic Sensory Neurons.

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