Department of Cell Biology, Capital Medical University and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Beijing, China.
Cell Death Differ. 2021 Apr;28(4):1174-1192. doi: 10.1038/s41418-020-00641-7. Epub 2020 Oct 27.
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 heterozygous ALR knockout 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 gene UBA2, 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 of UBA2. 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.
肝缺血再灌注损伤（IRI）是肝外科的常见并发症。虽然线粒体裂变和融合的失衡已被确定为 IRI 的原因，但详细的机制仍不清楚。肝再生增强因子（ALR）通过抑制与动力相关蛋白 1（Drp1）磷酸化来防止线粒体裂变，这在一定程度上有助于其肝脏保护作用。除了磷酸化，Drp1 的活性还受小泛素样修饰（SUMOylation）的调节，这加速了线粒体裂变。本研究旨在探讨 ALR 介导的肝 IRI 保护是否与 Drp1 SUMOylation 的作用有关。从人类和杂合 ALR 敲除小鼠的肝组织中采集肝组织，这些小鼠经历了 IRI。研究了 Drp1 的 SUMOylation 和磷酸化及其被 ALR 调节的情况。在人移植肝和小鼠 IRI 肝中，肝 Drp1 SUMOylation 显著增加。ALR 转染显著降低了 Drp1 SUMOylation，减轻了 IRI 诱导的线粒体裂变，维持了线粒体的稳定性和功能。本研究表明，转录因子 Yin Yang-1 (YY1)与其下游靶基因 UBA2 的结合对于控制 Drp1 SUMOylation 至关重要。UBA2 是 SUMO-E1 酶异二聚体的一个亚基。通过与 YY1 相互作用，ALR 抑制其核内输入，并显著降低 UBA2 的转录水平。因此，线粒体裂变明显减少，线粒体功能得到维持。本研究表明，ALR 对 Drp1 SUMOylation 的调节可防止线粒体裂变，从而使肝细胞免受 IRI 诱导的凋亡。这些新发现为临床干预提供了一个潜在的靶点，以减少肝外科手术中 IRI 的影响。
