Department of Biomedical Science & Engineering, Gwangju Institute of Science & Technology, Gwangju, Republic of Korea.
Institute of Environmental Health Sciences and Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, Michigan, USA.
Biofactors. 2021 Jan;47(1):112-125. doi: 10.1002/biof.1708. Epub 2021 Jan 26.
Peroxisomes are dynamic organelles that participate in a diverse array of cellular processes, including β-oxidation, which produces a considerable amount of reactive oxygen species (ROS). Although we showed that catalase depletion induces ROS-mediated pexophagy in cells, the effect of catalase deficiency during conditions that favor ROS generation remains elusive in mice. In this study, we reported that prolonged fasting in catalase-knockout (KO) mice drastically increased ROS production, which induced liver-specific pexophagy, an autophagic degradation of peroxisomes. In addition, increased ROS generation induced the production of pro-inflammatory cytokines in the liver tissues of catalase-KO mice. Furthermore, there was a significant increase in the levels of aspartate transaminase and alanine transaminase as well as apparent cell death in the liver of catalase-KO mice during prolonged fasting. However, an intra-peritoneal injection of the antioxidant N-acetyl-l-cysteine (NAC) and autophagy inhibitor chloroquine inhibited the inflammatory response, liver damage, and pexophagy in the liver of catalase-KO mice during prolonged fasting. Consistently, genetic ablation of autophagy, Atg5 led to suppression of pexophagy during catalase inhibition by 3-aminotriazole (3AT). Moreover, treatment with chloroquine also ameliorated the inflammatory response and cell death in embryonic fibroblast cells from catalase-KO mice. Taken together, our data suggest that ROS-mediated liver-specific pexophagy observed during prolonged fasting in catalase-KO mice may be responsible for the process associated with hepatic cell death.
过氧化物酶体是一种动态细胞器，参与多种细胞过程，包括β-氧化，该过程会产生大量的活性氧（ROS）。虽然我们已经表明，过氧化氢酶耗竭会诱导细胞中 ROS 介导的过氧化物酶体自噬，但在有利于 ROS 产生的条件下，过氧化氢酶缺乏对小鼠的影响仍不清楚。在这项研究中，我们报道了在过氧化氢酶敲除（KO）小鼠中长时间禁食会急剧增加 ROS 的产生，从而诱导肝脏特异性的过氧化物酶体自噬，即过氧化物酶体的自噬降解。此外，ROS 的产生增加会诱导过氧化氢酶 KO 小鼠肝组织中促炎细胞因子的产生。此外，在长时间禁食期间，过氧化氢酶 KO 小鼠的血清中天冬氨酸转氨酶和丙氨酸转氨酶水平明显升高，并且肝脏明显出现细胞死亡。然而，在长时间禁食期间，向过氧化氢酶 KO 小鼠腹腔内注射抗氧化剂 N-乙酰半胱氨酸（NAC）和自噬抑制剂氯喹可抑制炎症反应、肝损伤和过氧化物酶体自噬。一致地，在 3-氨基三唑（3AT）抑制过氧化氢酶时，自噬基因 Atg5 的缺失会抑制过氧化物酶体自噬。此外，氯喹处理也可改善过氧化氢酶 KO 小鼠胚胎成纤维细胞中的炎症反应和细胞死亡。总之，我们的数据表明，在过氧化氢酶 KO 小鼠长时间禁食期间观察到的 ROS 介导的肝脏特异性过氧化物酶体自噬可能是与肝细胞死亡相关过程的原因。
