Disturbance of mitochondrial dynamics and mitophagy in sepsis-induced acute kidney injury
Disturbance of mitochondrial dynamics and mitophagy in sepsis-induced acute kidney injury
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脓毒症引起的急性肾损伤中线粒体动力学和线粒体自噬的紊乱
DOI：
10.1016/j.lfs.2019.116828
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发表时间：
2019-10-15
期刊：
影响因子：
6.1
通讯作者：
Liu, Hua-feng
中科院分区：
文献类型：
--
作者：
Liu, Jian-xing;Yang, Chen;Liu, Hua-feng
目的：肾小管细胞在对化学梯度的重吸收和分泌过程中需要大量的线粒体来提供ATP，导致线粒体在应激条件下容易紊乱和损伤。损伤的线粒体最终通过线粒体自噬降解，线粒体自噬的紊乱与急性肾损伤（AKI）的发病机制有关，如糖尿病肾病和肾小球硬化。然而，线粒体自噬是否发生紊乱及其在SAKI中所起的作用尚不清楚。因此，本研究的目的是探讨脓毒症诱导的急性肾损伤（SAKI）中线粒体自噬和线粒体动力学的关键特征。主要方法：建立盲肠结扎穿刺（CLP）致小鼠脓毒性AKI模型；测定不同时间点小鼠肾脏线粒体自噬和线粒体动力学。主要发现：结果表明，线粒体动力学表现为裂变/融合异常，但更倾向于裂变，线粒体相关凋亡随着时间的推移而升高。此外，线粒体自噬在SAKI晚期受损，尽管在SAKI早期升高。结果表明，有丝分裂受损的潜在机制可能与NLRP3激活的半胱天冬酶裂解Parkin有关，至少部分相关。意义：可以想象，这种选择性自噬过程和质量控制机制受损，导致受损线粒体积累、氧化应激和细胞死亡。因此，通过加强SAKI期间的线粒体自噬，有针对性的方法可能是一种很有前途的治疗策略。
Aims: The renal tubule cells require a large number of mitochondria to supply ATP due to their high-energy demand during reabsorption and secretion against chemical gradients and result in mitochondria susceptible to disorder and injury during stress conditions. Injured mitochondria are eventually degraded by mitophagy, and disturbances in mitophagy are associated with the pathogenesis of acute kidney injury (AKI) such as diabetic nephropathy and glomerulosclerosis. However, whether a disturbance in mitophagy has occurred and the role it plays in (SAKI) is still unclear. Therefore, the aim of this study was to investigate the key features of mitophagy and mitochondrial dynamics in sepsis-induced acute kidney injury (SAKI).Main methods: In this study, a murine septic AKI model induced by cecal ligation and puncture (CLP) was built; mitophagy and mitochondrial dynamics were measured in mice kidney in different time point.Key findings: The results showed that mitochondrial dynamics were characterized by fission/fusion aberrant, however more inclined to fission, and mitochondrial associated apoptosis was elevated over-time during SAKI. Furthermore, mitophagy was impaired in the later phase of SAKI, although elevated in early stage of SAKI. The results indicate that the underlying mechanisms of impaired mitophagy may associate with the cleavage of Parkin via caspases activated by NLRP3, at least partly.Significance: It is conceivable that this selective autophagic process and quality control machinery was impaired, leading to the accumulation of damaged mitochondria, oxidative stress, and cell death. Therefore, a targeted approach, by enhancing mitophagy during SAKI, may be a promising therapeutic strategy.