Gil-Pitarch Clàudia, Serrano-Maciá Marina, Simon Jorge, Mosca Laura, Conter Carolina, Rejano-Gordillo Claudia M, Zapata-Pavas L Estefanía, Peña-Sanfélix Patricia, Azkargorta Mikel, Rodríguez-Agudo Rubén, Lachiondo-Ortega Sofía, Mercado-Gómez Maria, Delgado Teresa C, Porcelli Marina, Aurrekoetxea Igor, Sutherland James D, Barrio Rosa, Xirodimas Dimitris, Aspichueta Patricia, Elortza Felix, Martínez-Cruz Luis Alfonso, Nogueiras Rubén, Iruzubieta Paula, Crespo Javier, Masson Steven, McCain Misti Vanette, Reeves Helen L, Andrade Raul J, Lucena M Isabel, Mayor Ugo, Goikoetxea-Usandizaga Naroa, González-Recio Irene, Martínez-Chantar María L
Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain.
Department of Life Sciences, Health and Health Professions, Link University, Via del Casale di San Pio V, 44 00165 Rome, Italy.
Cell Rep Med. 2024 Jul 16;5(7):101653. doi: 10.1016/j.xcrm.2024.101653.
Drug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Here, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from patients with APAP-induced liver injury (AILI) and in mice treated with an APAP overdose. MLN4924, an inhibitor of the neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE-1), ameliorated necrosis and boosted liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 (NEDD8) and ubiquitin (UB) transgenic mice were investigated under APAP overdose with and without MLN4924. The cytidine diphosphate diacylglycerol (CDP-DAG) synthase TAM41, responsible for producing cardiolipin essential for mitochondrial activity, was found modulated under AILI and restored its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment.
药物性肝损伤（DILI）是西方世界急性肝衰竭（ALF）和肝移植的一个重要原因。对乙酰氨基酚（APAP）过量是DILI的主要促成因素，通过坏死导致肝细胞死亡。在此，我们发现，NEDD化（一种参与线粒体功能的重要翻译后修饰）在APAP诱导的肝损伤（AILI）患者的肝活检组织以及用APAP过量处理的小鼠中上调。MLN4924是神经元前体细胞表达的发育下调蛋白8（NEDD8）激活酶（NAE-1）的抑制剂，可改善AILI中的坏死并促进肝再生。为了解NEDD化如何干扰AILI，我们在有和没有MLN4924的情况下，对全身生物素化的NEDD8（NEDD8）和泛素（UB）转基因小鼠进行了APAP过量处理研究。发现负责产生线粒体活性所必需的心磷脂的胞苷二磷酸二酰甘油（CDP-DAG）合酶TAM41在AILI中受到调节，并通过抑制NEDD化恢复其水平。了解AILI中这种类泛素串扰对于开发有前景的DILI治疗靶向抑制剂至关重要。
