Uncoupled turnover disrupts mitochondrial quality control in diabetic retinopathy
Uncoupled turnover disrupts mitochondrial quality control in diabetic retinopathy
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DOI：
10.1172/jci.insight.129760
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发表时间：
2019-12-05
期刊：
影响因子：
8
通讯作者：
Xu, Heping
中科院分区：
文献类型：
--
作者：
Hombrebueno, Jose R.;Cairns, Lauren;Xu, Heping
线粒体质量控制（MQC）是调节中枢神经系统稳态的关键，其破坏与一些最常见的神经退行性疾病的发病机制有关。在健康组织中，MQC的维持取决于线粒体自噬（通过自噬去除受损的线粒体）和生物发生（线粒体的从头合成）之间的微妙平衡。在这里，我们表明，线粒体自噬在糖尿病视网膜病变（DR）中被破坏，并在疾病进展过程中与线粒体生物合成脱钩。来自人类死后供体和实验小鼠的糖尿病视网膜在疾病过程的早期阶段表现出线粒体含量的净损失。使用糖尿病线粒体自噬报告小鼠（mitoQC-Ins 2（秋田））和pMitoTimer（一种解决线粒体年龄动态的分子钟），我们证明了线粒体丢失是由于线粒体生物合成无法补偿糖尿病加重的线粒体自噬。然而，随着糖尿病持续时间的增加，Pink 1依赖性线粒体自噬恶化，导致DR中准备降解的线粒体的积累。长期糖尿病期间线粒体自噬的损害与视网膜衰老的发展有关，这是一种在mitoQC原代Muller细胞中钝化高血糖诱导的线粒体自噬的表型。我们的研究结果表明，正常化的线粒体周转可以保持MQC，并提供DR相关并发症的管理治疗选择。
Mitochondrial quality control (MQC) is crucial for regulating CNS homeostasis, and its disruption has been implicated in the pathogenesis of some of the most common neurodegenerative diseases. In healthy tissues, the maintenance of MQC depends upon an exquisite balance between mitophagy (removal of damaged mitochondria by autophagy) and biogenesis (de novo synthesis of mitochondria). Here, we show that mitophagy is disrupted in diabetic retinopathy (DR) and decoupled from mitochondrial biogenesis during the progression of the disease. Diabetic retinas from human postmortem donors and experimental mice exhibit a net loss of mitochondrial contents during the early stages of the disease process. Using diabetic mitophagy-reporter mice (mitoQC-Ins2(Akita)) alongside pMitoTimer (a molecular clock to address mitochondrial age dynamics), we demonstrate that mitochondrial loss arose due to an inability of mitochondrial biogenesis to compensate for diabetes-exacerbated mitophagy. However, as diabetes duration increases, Pink1-dependent mitophagy deteriorates, leading to the build-up of mitochondria primed for degradation in DR. Impairment of mitophagy during prolonged diabetes is linked with the development of retinal senescence, a phenotype that blunted hyperglycemia-induced mitophagy in mitoQC primary Muller cells. Our findings suggest that normalizing mitochondrial turnover may preserve MQC and provide therapeutic options for the management of DR-associated complications.