Novologue Therapy Requires Heat Shock Protein 70 and Thioredoxin-Interacting Protein to Improve Mitochondrial Bioenergetics and Decrease Mitophagy in Diabetic Sensory Neurons.
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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DOI：
10.1021/acschemneuro.1c00340
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发表时间：
2021-08-18
影响因子：
5
通讯作者：
Dobrowsky RT
中科院分区：
文献类型：
--
作者：
Rodriguez YA;Kaur S;Nolte E;Zheng Z;Blagg BSJ;Dobrowsky RT
糖尿病周围神经病变（DPN）是糖尿病的并发症，其病理生理学与线粒体生物能量学（mtBE）改变有关。KU-596是一种小分子神经治疗剂，可逆转DPN症状，改善感觉神经元MTBE，并以热休克蛋白70（Hsp 70）依赖性方式降低促氧化蛋白硫氧还蛋白相互作用蛋白（Txnip）。然而，KU-596改善MTBE的机制和Txnip在药物功效中的作用仍然未知。线粒体自噬是一种质量控制机制，它选择性地靶向受损的线粒体进行降解。本研究的目的是确定KU-596治疗是否以Hsp 70和Txnip依赖性方式改善DPN、MTBE和线粒体自噬。Mito-QC（MQC）小鼠表达一种能够可视化线粒体自噬的细胞靶向mCherry-GFP融合蛋白。糖尿病MQC、MQC × Hsp 70敲除（KO）和MQC × Txnip KO小鼠出现与DPN发作一致的感觉和神经传导功能障碍。KU-596治疗改善了这些测量，并且这依赖于Hsp 70而不是Txnip。在MQC小鼠中，糖尿病降低了mtBE，增加了线粒体自噬，KU-596治疗逆转了这些影响。相反，KU-596不能改善MQC × Hsp 70和MQC × Txnip KO小鼠的mtBE和减少线粒体自噬。这些数据表明，Txnip是不必要的感觉症状和线粒体功能障碍的糖尿病诱导的发展。KU-596治疗可以改善线粒体对糖尿病应激的耐受性，从而以Hsp 70和Txnip依赖性方式降低线粒体吞噬清除率。
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.
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DOI：
10.1083/jcb.201603039
发表时间：
2016-08-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
McWilliams TG;Prescott AR;Allen GF;Tamjar J;Munson MJ;Thomson C;Muqit MM;Ganley IG
通讯作者：
Ganley IG
影响因子：
4.2
作者：
Lautrup, Sofie;Lou, Guofeng;Fang, Evandro F.
通讯作者：
Fang, Evandro F.
影响因子：
4.7
作者：
Li, Chengyuan;Ma, Jiacheng;Dobrowsky, Rick T.
通讯作者：
Dobrowsky, Rick T.
影响因子：
9
作者：
Devi TS;Somayajulu M;Kowluru RA;Singh LP
通讯作者：
Singh LP
影响因子：
5
作者：
Ma, Jiacheng;Pan, Pan;Dobrowsky, Rick T.
通讯作者：
Dobrowsky, Rick T.