Augmenter of liver regeneration-mediated mitophagy protects against hepatic ischemia/reperfusion injury
Augmenter of liver regeneration-mediated mitophagy protects against hepatic ischemia/reperfusion injury
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DOI：
10.1111/ajt.16757
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发表时间：
2021-08-05
影响因子：
8.8
通讯作者：
An, Wei
中科院分区：
文献类型：
--
作者：
Kong, Wei-ning;Li, Wen;An, Wei
肝再生增强因子（Augmenter of liver regeneration， ALR）是一种主要存在于线粒体中的抗凋亡蛋白。它可以保护肝细胞免受缺血再灌注（I/R）损伤，但其潜在机制尚不清楚。我们发现，在大鼠原位肝移植过程中，ALR基因的传递减轻了肝脏I/R损伤，这可以通过降低血清转氨酶、氧化应激和细胞凋亡以及增加自噬标志物的表达来证明。在体外缺氧/再氧化（H/R）模型中，ALR基因的过表达激活了自噬，并通过PINK1/Parkin途径缓解了缺陷的有丝分裂。在机制上，ALR转染诱导H/R模型中mitofusin 2 （Mfn2）的表达，导致Parkin的PINK1积累和线粒体易位。Mfn2的缺失消除了ALR转染诱导的线粒体自噬激活，促进线粒体功能障碍，最终增加细胞凋亡。Mfn2可抑制alr敲除（KO）细胞的线粒体自噬，从而减轻线粒体功能障碍和细胞凋亡。在热I/R损伤的杂合alr敲除小鼠中，肝损伤的明显加重与线粒体自噬抑制和Mfn2表达降低有关。综上所述，我们的研究结果证实，ALR通过Mfn2加速Parkin易位和线粒体自噬，并保护肝细胞免受I/ r诱导的损伤。我们的发现为肝I/R损伤的治疗提供了新的理论依据。
Augmenter of liver regeneration (ALR) is an anti-apoptotic protein found mainly in mitochondria. It protects hepatocytes from ischemia-reperfusion (I/R) injury, but the underlying mechanism is not clear. We found that in rats, delivery of the ALR gene alleviated hepatic I/R injury during orthotopic liver transplantation as evidenced by reduced serum aminotransferase, oxidative stress and apoptosis, and increased expression of autophagy markers. In an in vitro hypoxia/reoxygenation (H/R) model, overexpression of the ALR gene activated autophagy and relieved defective mitophagy via the PINK1/Parkin pathway. Mechanistically, ALR transfection induced the expression of mitofusin 2 (Mfn2) in the H/R model, which led to PINK1 accumulation and mitochondrial translocation of Parkin. Deletion of Mfn2 abolished mitophagy activation induced by ALR transfection, promoted mitochondrial dysfunction, and eventually increased cell apoptosis. Mfn2 administration prevented the inhibition of mitophagy in ALR-knockout (KO) cells, thus attenuated mitochondrial dysfunction and cell apoptosis. In heterozygous ALR-knockout mice treated with a warm I/R injury, marked aggravation of liver injury was associated with mitophagy inhibition and reduction in Mfn2 expression. Taken together, our results confirm that ALR accelerated Parkin translocation and mitophagy via Mfn2, and protected hepatocytes from I/R-induced injury. Our findings provide a novel rationale for the treatment of hepatic I/R injury.