Qian Meizi, Zhu Yurun, Lin Wen, Lian Huidan, Xia Yun, Papadimos Thomas, Wang Junlu
The First Affiliated Hospital of Wenzhou Medical University, Department of Anesthesiology, Wenzhou City, Zhejiang Province, China; Key Laboratory of Intelligent Treatment and Life Support for Critical Diseases of Zhejiang Province, Wenzhou 325000, Zhejiang, China.
The First Affiliated Hospital of Wenzhou Medical University, Department of Anesthesiology, Wenzhou City, Zhejiang Province, China.
Int Immunopharmacol. 2025 May 27;156:114685. doi: 10.1016/j.intimp.2025.114685. Epub 2025 Apr 25.
Mitochondria are important targets for preventing oxidative damage during the progression of sepsis-induced lung injury. Numerous studies have pointed out that maintaining the stabilization of Nrf-2, thereby activating its transcription, may combat pathological inflammation by sustaining the integrity of mitochondrial function. Our previous study found that protein interaction with C-kinase 1 (PICK1) deficiency disrupts the physiological anti-inflammatory mechanism by affecting Nrf-2 transcription. However, whether PICK1 participates in mitochondrial quality control regulation through Nrf-2 has not been explored, and the underlying interaction between PICK1 and Nrf-2 has not been fully elucidated. We found that PICK1 decreased mitochondria-derived ROS, upregulated MnSOD activity in endotoxin-induced acute lung injury mice, improved mitochondrial membrane potential, and restored the damaged structure of mitochondria in LPS-stimulated macrophages. Through in-depth studies, we demonstrated that PICK1 maintains the stability of Nrf-2 by preserving mitochondrial dynamic equilibrium, facilitating mitochondrial biogenesis, and participating in mitophagy by activating the PI3K/AKT/GSK-3β pathway. PICK1 also inhibits the β-TrCP-mediated ubiquitination of Nrf-2. Thus, PICK1 offers an unexplored alternative to current Nrf-2 activators by acting as a Nrf-2 activator that may have therapeutic value against septic inflammation. Our study demonstrated the protective effects of PICK1 overexpression in endotoxin-associated ALI. PICK1 overexpression and the subsequent PI3K/AKT/Nrf-2/HO-1 pathway-dependent and E3 ubiquitin ligase adapter β-TrCP-mediated mitochondrial quality control contribute to lung repair, which offers an unexplored alternative to current Nrf-2 activators by acting as a Nrf-2 activator that may have therapeutic value against septic inflammation.
线粒体是脓毒症诱导的肺损伤进展过程中预防氧化损伤的重要靶点。大量研究指出，维持核因子E2相关因子2（Nrf-2）的稳定性，从而激活其转录，可能通过维持线粒体功能的完整性来对抗病理性炎症。我们之前的研究发现，与C激酶1相互作用的蛋白（PICK1）缺乏会通过影响Nrf-2转录破坏生理抗炎机制。然而，PICK1是否通过Nrf-2参与线粒体质量控制调节尚未得到探索，且PICK1与Nrf-2之间的潜在相互作用也未完全阐明。我们发现，在脂多糖诱导的急性肺损伤小鼠中，PICK1可降低线粒体衍生的活性氧（ROS），上调锰超氧化物歧化酶（MnSOD）活性，改善线粒体膜电位，并恢复脂多糖刺激的巨噬细胞中受损的线粒体结构。通过深入研究，我们证明PICK1通过维持线粒体动态平衡、促进线粒体生物发生以及激活磷脂酰肌醇-3激酶（PI3K）/蛋白激酶B（AKT）/糖原合成酶激酶-3β（GSK-3β）途径参与线粒体自噬，从而维持Nrf-2的稳定性。PICK1还抑制β-转导素重复序列包含蛋白（β-TrCP）介导的Nrf-2泛素化。因此，PICK1作为一种可能对脓毒症炎症具有治疗价值的Nrf-2激活剂，为目前的Nrf-2激活剂提供了一种未被探索的替代方案。我们的研究证明了PICK1过表达在内毒素相关急性肺损伤中的保护作用。PICK1过表达以及随后依赖PI3K/AKT/Nrf-2/血红素加氧酶-1（HO-1）途径和E3泛素连接酶衔接蛋白β-TrCP介导的线粒体质量控制有助于肺修复，这作为一种可能对脓毒症炎症具有治疗价值的Nrf-2激活剂，为目前的Nrf-2激活剂提供了一种未被探索的替代方案。
