Inhibition of Drp1 SUMOylation by ALR protects the liver from ischemia-reperfusion injury
Inhibition of Drp1 SUMOylation by ALR protects the liver from ischemia-reperfusion injury
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ALR 抑制 Drp1 SUMO 化可保护肝脏免受缺血再灌注损伤
DOI：
10.1038/s41418-020-00641-7
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发表时间：
2020-10-27
影响因子：
12.4
通讯作者：
An, Wei
中科院分区：
文献类型：
--
作者：
Huang, Jing;Xie, Ping;An, Wei
肝脏缺血再灌注损伤（IRI）是肝脏外科常见的并发症。虽然线粒体分裂和融合之间的不平衡已被确定为IRI的原因，但详细的机制仍不清楚。据报道，肝再生增强因子（ALR）通过抑制动力蛋白相关蛋白1（Drp 1）磷酸化来防止线粒体分裂，部分有助于其肝脏保护。除了磷酸化，Drp 1的活性还受到小的泛素样修饰（SUMO化）的调节，这加速了线粒体的分裂。本研究旨在研究ALR介导的肝脏IRI保护作用是否与Drp 1 SUMO化作用相关。从人类和异源性ALRknockout小鼠中收获肝组织，这些小鼠进行IRI。研究了Drp 1的SUMO化和磷酸化以及ALR对其的调节作用。在人肝移植和小鼠IRI肝中，Drp 1 SUMO化水平显著升高，ALR转染可显著降低Drp 1 SUMO化水平，减弱IRI诱导的线粒体分裂，保护线粒体的稳定性和功能。本研究表明，转录因子Yin Yang-1（YY 1）与其下游靶基因UBA 2（SUMO-E1酶异源二聚体的亚基）的结合是控制Drp 1 SUMO化的关键。通过与YY 1相互作用，ALR抑制其核输入并显著降低UBA 2的转录水平。因此，线粒体分裂显著减少，线粒体功能得以维持。这项研究表明，ALR对Drp 1 SUMO化的调节保护线粒体免于分裂，拯救肝细胞免于IRI诱导的凋亡。这些新的发现为临床干预提供了一个潜在的目标，以减少肝脏手术期间IRI的影响。
Hepatic ischemic reperfusion injury (IRI) is a common complication of liver surgery. Although an imbalance between mitochondrial fission and fusion has been identified as the cause of IRI, the detailed mechanism remains unclear. Augmenter of liver regeneration (ALR) was reported to prevent mitochondrial fission by inhibiting dynamin-related protein 1 (Drp1) phosphorylation, contributing partially to its liver protection. Apart from phosphorylation, Drp1 activity is also regulated by small ubiquitin-like modification (SUMOylation), which accelerates mitochondrial fission. This study aimed to investigate whether ALR-mediated protection from hepatic IRI might be associated with an effect on Drp1 SUMOylation. Liver tissues were harvested from both humans and from heterozygousALRknockout mice, which underwent IRI. The SUMOylation and phosphorylation of Drp1 and their modulation by ALR were investigated. Hepatic Drp1 SUMOylation was significantly increased in human transplanted livers and IRI-livers of mice.ALR-transfection significantly decreased Drp1 SUMOylation, attenuated the IRI-induced mitochondrial fission and preserved mitochondrial stability and function. This study showed that the binding of transcription factor Yin Yang-1 (YY1) to its downstream target geneUBA2, a subunit of SUMO-E1 enzyme heterodimer, was critical to control Drp1 SUMOylation. By interacting with YY1, ALR inhibits its nuclear import and dramatically decreases the transcriptional level ofUBA2. Consequently, mitochondrial fission was significantly reduced, and mitochondrial function was maintained. This study showed that the regulation of Drp1 SUMOylation by ALR protects mitochondria from fission, rescuing hepatocytes from IRI-induced apoptosis. These new findings provide a potential target for clinical intervention to reduce the effects of IRI during hepatic surgery.