PDF(Pubmed)
Abstract：
Mitochondrial dysfunction is a key pathological event in the acute liver injury following the overdose of acetaminophen (APAP). Calpain is the calcium-dependent protease, recent studies demonstrate that it is involved in the impairment of mitochondrial dynamics. The mitochondrial unfolded protein response (UPRmt) is commonly activated in the context of mitochondrial damage following pathological insults and contributes to the maintenance of the mitochondrial quality control through regulating a wide range of gene expression. More importantly, it is reported that abnormal aggregation of TDP-43 in mitochondria induced the activation of UPRmt. However, whether it is involved in APAP induced-hepatotoxicity remains unclear. In the present study, C57/BL6 mice were given 300 mg/kg APAP to establish a time-course model of acute liver injury. Furthermore, Calpeptin, the specific inhibiter of calpains, was used to conduct the intervention experiment. Our results showed, APAP exposure produced severe liver injury. Moreover, TDP-43 was obviously accumulated within mitochondria whereas mitochondrial protease LonP1 was significantly decreased. However, these changes exhibited significant recovery at 48 h. By contrast, the mitochondrial protease ClpP and chaperone mtHSP70 and HSP60 were consistently increased, which supported the UPRmt was activated to promote protein homeostasis. Further investigation revealed that calpain-mediated cleavage of TDP-43 could promote the accumulation of TDP-43 in mitochondria compartment, thereby facilitating the activation of UPRmt. Additionally, Calpeptin pretreatment not only protected against APAP-induced liver injury, but also suppressed the formation of TDP-43 aggregates and the activation of UPRmt. Taken together, our findings indicated that in APAP-induced acute liver injury, calpain-mediated cleavage of TDP43 caused its aberrant aggregation on the mitochondria. As a stress-protective response, the induction of UPRmt contributed to the recovery of mitochondrial function.
摘要：
线粒体功能障碍是对乙酰氨基酚（APAP）过量后急性肝损伤的关键病理事件。钙蛋白酶是钙依赖性蛋白酶,最近的研究表明，它与线粒体动力学的损害有关。线粒体未折叠蛋白反应(UPRmt)通常在病理性损伤后的线粒体损伤的情况下被激活,并且通过调节宽范围的基因表达有助于维持线粒体质量控制。更重要的是,据报道，线粒体中TDP-43的异常聚集诱导了UPRmt的激活。然而,是否参与APAP诱导的肝毒性尚不清楚.在本研究中,C57/BL6小鼠给予300mg/kgAPAP建立急性肝损伤时程模型。此外，Calpeptin,钙蛋白酶的特定抑制剂，用于进行干预实验。我们的结果显示,APAP暴露导致严重的肝损伤。此外，TDP-43在线粒体内明显积累，而线粒体蛋白酶LonP1明显减少。然而,这些变化在48小时表现出显著的恢复。相比之下，线粒体蛋白酶ClpP和伴侣mtHSP70和HSP60持续增加，这支持UPRmt被激活以促进蛋白质稳态。进一步研究表明，钙蛋白酶介导的TDP-43裂解可以促进TDP-43在线粒体小室的积累，从而促进UPRmt的激活。此外,Calpeptin预处理不仅可以预防APAP引起的肝损伤，但也抑制了TDP-43聚集体的形成和UPRmt的激活。一起来看,我们的研究结果表明，在APAP诱导的急性肝损伤，钙蛋白酶介导的TDP43裂解导致其在线粒体上的异常聚集。作为一种压力保护反应，UPRmt的诱导有助于线粒体功能的恢复。
